Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células

ilustraciones, graficas

Autores:
Lalinde Ruiz, Nicolás
Tipo de recurso:
Fecha de publicación:
2022
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/82620
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/82620
https://repositorio.unal.edu.co/
Palabra clave:
610 - Medicina y salud
Linfocitos T
Técnicas In Vitro
T-Lymphocytes
In Vitro Techniques
Terapia adoptiva de células
Memoria
Linfocitos T CD4
Vacunación
Linfocitos T foliculares helper
Adoptive cell therapy
Memory
CD4 T lymphocytes
Vaccination
Helper Follicular T Lymphocytes
Rights
openAccess
License
Reconocimiento 4.0 Internacional
id UNACIONAL2_e3279b89a95e2e5d588c6297993f6685
oai_identifier_str oai:repositorio.unal.edu.co:unal/82620
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células
dc.title.translated.eng.fl_str_mv Determination of in-vitro conditions to expand stem memory T Cells for adoptive cell therapy
title Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células
spellingShingle Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células
610 - Medicina y salud
Linfocitos T
Técnicas In Vitro
T-Lymphocytes
In Vitro Techniques
Terapia adoptiva de células
Memoria
Linfocitos T CD4
Vacunación
Linfocitos T foliculares helper
Adoptive cell therapy
Memory
CD4 T lymphocytes
Vaccination
Helper Follicular T Lymphocytes
title_short Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células
title_full Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células
title_fullStr Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células
title_full_unstemmed Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células
title_sort Determinación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de células
dc.creator.fl_str_mv Lalinde Ruiz, Nicolás
dc.contributor.advisor.none.fl_str_mv Parra López, Carlos Alberto
dc.contributor.author.none.fl_str_mv Lalinde Ruiz, Nicolás
dc.contributor.researchgroup.spa.fl_str_mv Inmunología y Medicina Traslacional
dc.subject.ddc.spa.fl_str_mv 610 - Medicina y salud
topic 610 - Medicina y salud
Linfocitos T
Técnicas In Vitro
T-Lymphocytes
In Vitro Techniques
Terapia adoptiva de células
Memoria
Linfocitos T CD4
Vacunación
Linfocitos T foliculares helper
Adoptive cell therapy
Memory
CD4 T lymphocytes
Vaccination
Helper Follicular T Lymphocytes
dc.subject.other.spa.fl_str_mv Linfocitos T
Técnicas In Vitro
dc.subject.other.eng.fl_str_mv T-Lymphocytes
In Vitro Techniques
dc.subject.proposal.spa.fl_str_mv Terapia adoptiva de células
Memoria
Linfocitos T CD4
Vacunación
Linfocitos T foliculares helper
dc.subject.proposal.eng.fl_str_mv Adoptive cell therapy
Memory
CD4 T lymphocytes
Vaccination
Helper Follicular T Lymphocytes
description ilustraciones, graficas
publishDate 2022
dc.date.accessioned.none.fl_str_mv 2022-11-03T15:09:45Z
dc.date.available.none.fl_str_mv 2022-11-03T15:09:45Z
dc.date.issued.none.fl_str_mv 2022-09-27
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/82620
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/82620
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.indexed.spa.fl_str_mv RedCol
LaReferencia
dc.relation.references.spa.fl_str_mv Perica K, Varela JC, Oelke M, Schneck J. Adoptive T cell immunotherapy for cancer. Rambam Maimonides medical journal. 2015;6(1):e0004.
Rohaan MW, Wilgenhof S, Haanen J. Adoptive cellular therapies: the current landscape. Virchows Archiv : an international journal of pathology. 2019;474(4):449-61.
Kondo T, Imura Y, Chikuma S, Hibino S, Omata-Mise S, Ando M, et al. Generation and application of human induced-stem cell memory T cells for adoptive immunotherapy. Cancer science. 2018;109(7):2130-40.
Esfahani K, Roudaia L, Buhlaiga N, Del Rincon SV, Papneja N, Miller WH, Jr. A review of cancer immunotherapy: from the past, to the present, to the future. Current oncology. 2020;27(Suppl 2):S87-S97.
Morotti M, Albukhari A, Alsaadi A, Artibani M, Brenton JD, Curbishley SM, et al. Promises and challenges of adoptive T-cell therapies for solid tumours. British journal of cancer. 2021;124(11):1759-76.
Dafni U, Michielin O, Lluesma SM, Tsourti Z, Polydoropoulou V, Karlis D, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Annals of oncology : official journal of the European Society for Medical Oncology. 2019;30(12):1902-13.
June CH. Adoptive T cell therapy for cancer in the clinic. The Journal of clinical investigation. 2007;117(6):1466-76.
Met O, Jensen KM, Chamberlain CA, Donia M, Svane IM. Principles of adoptive T cell therapy in cancer. Seminars in immunopathology. 2019;41(1):49-58.
Crompton JG, Sukumar M, Restifo NP. Uncoupling T-cell expansion from effector differentiation in cell-based immunotherapy. Immunological reviews. 2014;257(1):264-76.
Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. The Journal of clinical investigation. 2005;115(6):1616-26.
Spolski R, Gromer D, Leonard WJ. The gamma c family of cytokines: fine-tuning signals from IL-2 and IL-21 in the regulation of the immune response. F1000Research. 2017;6:1872.
Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2013;121(4):573-84.
Pietrobon V, Todd LA, Goswami A, Stefanson O, Yang Z, Marincola F. Improving CAR T-Cell Persistence. International journal of molecular sciences. 2021;22(19).
Hegde PS, Chen DS. Top 10 Challenges in Cancer Immunotherapy. Immunity. 2020;52(1):17-35.
Taefehshokr S, Parhizkar A, Hayati S, Mousapour M, Mahmoudpour A, Eleid L, et al. Cancer immunotherapy: Challenges and limitations. Pathology, research and practice. 2022;229:153723.
Arcangeli S, Falcone L, Camisa B, De Girardi F, Biondi M, Giglio F, et al. Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients. Frontiers in immunology. 2020;11:1217.
Majzner RG, Mackall CL. Clinical lessons learned from the first leg of the CAR T cell journey. Nature medicine. 2019;25(9):1341-55.
Li Y, Wu D, Yang X, Zhou S. Immunotherapeutic Potential of T Memory Stem Cells. Frontiers in oncology. 2021;11:723888.
Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nature reviews Immunology. 2002;2(4):251-62.
Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348(6230):62-8.
Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233(4770):1318-21.
Belldegrun A, Muul LM, Rosenberg SA. Interleukin 2 expanded tumor-infiltrating lymphocytes in human renal cell cancer: isolation, characterization, and antitumor activity. Cancer research. 1988;48(1):206-14.
Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(32):5233-9.
Busch DH, Frassle SP, Sommermeyer D, Buchholz VR, Riddell SR. Role of memory T cell subsets for adoptive immunotherapy. Seminars in immunology. 2016;28(1):28-34.
Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708-12.
Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. Journal of immunology. 1993;150(3):1122-36.
Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature medicine. 2009;15(7):808-13.
Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al. A human memory T cell subset with stem cell-like properties. Nature medicine. 2011;17(10):1290-7.
Kwok WW, Tan V, Gillette L, Littell CT, Soltis MA, LaFond RB, et al. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. Journal of immunology. 2012;188(6):2537-44.
Gattinoni L, Speiser DE, Lichterfeld M, Bonini C. T memory stem cells in health and disease. Nature medicine. 2017;23(1):18-27.
Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001;291(5512):2413-7.
Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who's who of T-cell differentiation: human memory T-cell subsets. European journal of immunology. 2013;43(11):2797-809.
Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nature immunology. 2003;4(3):225-34.
Ahmed R, Bevan MJ, Reiner SL, Fearon DT. The precursors of memory: models and controversies. Nature reviews Immunology. 2009;9(9):662-8.
Gasper DJ, Tejera MM, Suresh M. CD4 T-cell memory generation and maintenance. Critical reviews in immunology. 2014;34(2):121-46.
Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? Journal of immunotherapy. 2012;35(9):651-60.
Joshi NS, Kaech SM. Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. Journal of immunology. 2008;180(3):1309-15.
Lanzavecchia A, Sallusto F. Progressive differentiation and selection of the fittest in the immune response. Nature reviews Immunology. 2002;2(12):982-7.
Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science. 2007;315(5819):1687-91.
Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nature reviews Cancer. 2012;12(10):671-84.
Simons BD, Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell. 2011;145(6):851-62.
Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nature reviews Immunology. 2009;9(7):480-90.
Jicha DL, Mule JJ, Rosenberg SA. Interleukin 7 generates antitumor cytotoxic T lymphocytes against murine sarcomas with efficacy in cellular adoptive immunotherapy. The Journal of experimental medicine. 1991;174(6):1511-5.
Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636-45.
Toe JG, Pellegrini M, Mak TW. Promoting immunity during chronic infection--the therapeutic potential of common gamma-chain cytokines. Molecular immunology. 2013;56(1-2):38-47.
Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995;2(4):331-9.
Rathmell JC, Farkash EA, Gao W, Thompson CB. IL-7 enhances the survival and maintains the size of naive T cells. Journal of immunology. 2001;167(12):6869-76.
Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature reviews Immunology. 2006;6(8):595-601.
Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. Journal of immunology. 2005;175(12):7867-79.
Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. Journal of immunology. 2004;173(9):5361-71.
Chen Y, Yu F, Jiang Y, Chen J, Wu K, Chen X, et al. Adoptive Transfer of Interleukin-21-stimulated Human CD8+ T Memory Stem Cells Efficiently Inhibits Tumor Growth. Journal of immunotherapy. 2018;41(6):274-83.
Alvarez-Fernandez C, Escriba-Garcia L, Vidal S, Sierra J, Briones J. A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy. Journal of translational medicine. 2016;14(1):214.
Nakayamada S, Takahashi H, Kanno Y, O'Shea JJ. Helper T cell diversity and plasticity. Current opinion in immunology. 2012;24(3):297-302.
Pepper M, Pagan AJ, Igyarto BZ, Taylor JJ, Jenkins MK. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity. 2011;35(4):583-95.
Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nature immunology. 2011;12(6):467-71.
He J, Tsai LM, Leong YA, Hu X, Ma CS, Chevalier N, et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity. 2013;39(4):770-81.
Vinuesa CG, Linterman MA, Yu D, MacLennan IC. Follicular Helper T Cells. Annual review of immunology. 2016;34:335-68.
Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. The Journal of experimental medicine. 2000;192(11):1545-52.
Bowen MB, Butch AW, Parvin CA, Levine A, Nahm MH. Germinal center T cells are distinct helper-inducer T cells. Human immunology. 1991;31(1):67-75.
Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000;406(6793):309-14.
Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 1996;87(6):1037-47.
Walker LS, Gulbranson-Judge A, Flynn S, Brocker T, Raykundalia C, Goodall M, et al. Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers. The Journal of experimental medicine. 1999;190(8):1115-22.
King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annual review of immunology. 2008;26:741-66.
Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, et al. Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39(4):758-69.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annual review of immunology. 2008;26:677-704.
Jeza VT, Li X, Chen J, Liang Z, Aggrey AO, Wu X. IL-21 Augments Rapamycin in Expansion of Alpha Fetoprotein Antigen Specific Stem-Cell-like Memory T Cells in vitro. The Pan African medical journal. 2017;27:163.
Mueller SN, Gebhardt T, Carbone FR, Heath WR. Memory T cell subsets, migration patterns, and tissue residence. Annual review of immunology. 2013;31:137-61.
Olenchock BA, Rathmell JC, Vander Heiden MG. Biochemical Underpinnings of Immune Cell Metabolic Phenotypes. Immunity. 2017;46(5):703-13.
Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38(4):633-43.
Buck MD, O'Sullivan D, Pearce EL. T cell metabolism drives immunity. The Journal of experimental medicine. 2015;212(9):1345-60.
Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013;38(2):225-36.
Araujo L, Khim P, Mkhikian H, Mortales CL, Demetriou M. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife. 2017;6.
Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342(6155):1242454.
O'Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD, et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014;41(1):75-88.
van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.
Vella LA, Buggert M, Manne S, Herati RS, Sayin I, Kuri-Cervantes L, et al. T follicular helper cells in human efferent lymph retain lymphoid characteristics. The Journal of clinical investigation. 2019;129(8):3185-200.
Kared H, Tan SW, Lau MC, Chevrier M, Tan C, How W, et al. Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway. Nature communications. 2020;11(1):821.
Bai J, Gao Z, Li X, Dong L, Han W, Nie J. Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget. 2017;8(66):110693-707.
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. International immunology. 1996;8(5):765-72.
Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, et al. Expression of programmed death 1 ligands by murine T cells and APC. Journal of immunology. 2002;169(10):5538-45.
DiPiazza A, Richards KA, Knowlden ZA, Nayak JL, Sant AJ. The Role of CD4 T Cell Memory in Generating Protective Immunity to Novel and Potentially Pandemic Strains of Influenza. Frontiers in immunology. 2016;7:10.
Spolski R, Leonard WJ. Interleukin-21: a double-edged sword with therapeutic potential. Nature reviews Drug discovery. 2014;13(5):379-95.
Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408(6808):57-63.
Bugya Z, Prechl J, Szenasi T, Nemes E, Bacsi A, Koncz G. Multiple Levels of Immunological Memory and Their Association with Vaccination. Vaccines. 2021;9(2).
Fuertes Marraco SA, Soneson C, Cagnon L, Gannon PO, Allard M, Abed Maillard S, et al. Long-lasting stem cell-like memory CD8+ T cells with a naive-like profile upon yellow fever vaccination. Science translational medicine. 2015;7(282):282ra48.
da Silva Antunes R, Paul S, Sidney J, Weiskopf D, Dan JM, Phillips E, et al. Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses. PloS one. 2017;12(1):e0169086.
Mayer S, Laumer M, Mackensen A, Andreesen R, Krause SW. Analysis of the immune response against tetanus toxoid: enumeration of specific T helper cells by the Elispot assay. Immunobiology. 2002;205(3):282-9.
Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immunity & ageing : I & A. 2019;16:25.
Pereira B, Xu XN, Akbar AN. Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly. Frontiers in immunology. 2020;11:583019.
Rodriguez IJ, Lalinde Ruiz N, Llano Leon M, Martinez Enriquez L, Montilla Velasquez MDP, Ortiz Aguirre JP, et al. Immunosenescence Study of T Cells: A Systematic Review. Frontiers in immunology. 2020;11:604591.
Bruggner RV, Bodenmiller B, Dill DL, Tibshirani RJ, Nolan GP. Automated identification of stratifying signatures in cellular subpopulations. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(26):E2770-7.
Ding ZC, Shi H, Aboelella NS, Fesenkova K, Park EJ, Liu Z, et al. Persistent STAT5 activation reprograms the epigenetic landscape in CD4(+) T cells to drive polyfunctionality and antitumor immunity. Science immunology. 2020;5(52).
Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325(5943):1006-10.
Martinez GJ, Hu JK, Pereira RM, Crampton JS, Togher S, Bild N, et al. Cutting Edge: NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection. Journal of immunology. 2016;196(5):2015-9.
Salerno F, Turner M, Wolkers MC. Dynamic Post-Transcriptional Events Governing CD8(+) T Cell Homeostasis and Effector Function. Trends in immunology. 2020;41(3):240-54.
Tough DF, Rioja I, Modis LK, Prinjha RK. Epigenetic Regulation of T Cell Memory: Recalling Therapeutic Implications. Trends in immunology. 2020;41(1):29-45.
Corrado M, Pearce EL. Targeting memory T cell metabolism to improve immunity. The Journal of clinical investigation. 2022;132(1).
Li W, Zhang L. Rewiring Mitochondrial Metabolism for CD8(+) T Cell Memory Formation and Effective Cancer Immunotherapy. Frontiers in immunology. 2020;11:1834.
Zorova LD, Popkov VA, Plotnikov EY, Silachev DN, Pevzner IB, Jankauskas SS, et al. Mitochondrial membrane potential. Analytical biochemistry. 2018;552:50-9.
McKinstry KK, Strutt TM, Swain SL. Regulation of CD4+ T-cell contraction during pathogen challenge. Immunological reviews. 2010;236:110-24.
Zhan Y, Carrington EM, Zhang Y, Heinzel S, Lew AM. Life and Death of Activated T Cells: How Are They Different from Naive T Cells? Frontiers in immunology. 2017;8:1809.
Jameson SC, Masopust D. Understanding Subset Diversity in T Cell Memory. Immunity. 2018;48(2):214-26.
Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation. The Journal of experimental medicine. 2012;209(2):243-50.
Lalinde-Ruiz N, Rodriguez IJ, Bernal-Estevez DA, Parra-Lopez CA. Young but not older adults exhibit an expansion of CD45RA(+)CCR7(+)CD95(+) T follicular helper cells in response to tetanus vaccine. Experimental gerontology. 2021;156:111599.
Rovini A, Heslop K, Hunt EG, Morris ME, Fang D, Gooz M, et al. Quantitative analysis of mitochondrial membrane potential heterogeneity in unsynchronized and synchronized cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2021;35(1):e21148.
Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. Journal of immunology. 2008;181(7):4832-9.
Quintelier K, Couckuyt A, Emmaneel A, Aerts J, Saeys Y, Van Gassen S. Analyzing high-dimensional cytometry data using FlowSOM. Nature protocols. 2021;16(8):3775-801.
Schmitt N, Bentebibel SE, Ueno H. Phenotype and functions of memory Tfh cells in human blood. Trends in immunology. 2014;35(9):436-42.
Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nature reviews Immunology. 2016;16(2):102-11.
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.license.spa.fl_str_mv Reconocimiento 4.0 Internacional
dc.rights.uri.spa.fl_str_mv http://creativecommons.org/licenses/by/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv Reconocimiento 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.spa.fl_str_mv 154 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv Bogotá - Medicina - Maestría en Inmunología
dc.publisher.faculty.spa.fl_str_mv Facultad de Medicina
dc.publisher.place.spa.fl_str_mv Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv Universidad Nacional de Colombia - Sede Bogotá
institution Universidad Nacional de Colombia
bitstream.url.fl_str_mv https://repositorio.unal.edu.co/bitstream/unal/82620/1/license.txt
https://repositorio.unal.edu.co/bitstream/unal/82620/2/1018467284.%202022.pdf
https://repositorio.unal.edu.co/bitstream/unal/82620/3/1018467284.%202022.pdf.jpg
bitstream.checksum.fl_str_mv eb34b1cf90b7e1103fc9dfd26be24b4a
e57e5f9a2c15d51ec02b55cd479ee261
f881abafb882fb5ba47a4fb771279669
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
repository.mail.fl_str_mv repositorio_nal@unal.edu.co
_version_ 1814089705686302720
spelling Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Parra López, Carlos Alberto72ac583cfa47cd3a2fb760ecf10befccLalinde Ruiz, Nicolás4f43235a46ea62c29e9ecfac6d097d10Inmunología y Medicina Traslacional2022-11-03T15:09:45Z2022-11-03T15:09:45Z2022-09-27https://repositorio.unal.edu.co/handle/unal/82620Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, graficasLa terapia adoptiva de células tiene el potencial de aumentar la inmunidad antitumoral, al modificar las células in-vitro para expandir linfocitos que reconozcan y ataquen el tumor. La capacidad funcional y sobrevida de las células transferidas al paciente dependerá de las subpoblaciones de memoria que sean expandidas en el laboratorio, por lo que la obtención de células de memoria poco diferenciadas es deseable. El objetivo principal de este trabajo fue determinar una estrategia de expansión in-vitro de linfocitos T CD4 stem de memoria humanos. Partiendo de células vírgenes estimuladas con un agente policlonal y adicionando diferentes combinaciones de citoquinas de la familia gamma común, se encontró que la combinación de IL-7, IL-15 e IL-21 o IL-7 e IL-21 fueron los cócteles que produjeron una mayor cantidad de células con fenotipo stem de memoria, medido por citometría de flujo. Adicionalmente, a través de la medición de proteínas de membrana y análisis in-sillico, se estableció una estrecha relación de los linfocitos T stem de memoria con el programa de diferenciación de linfocitos T foliculares, lo que consideramos contribuye a un mejor entendimiento de los procesos que subyacen la generación y mantenimiento de la memoria y, por ende, puede mejorar las estrategias actuales de expansión de linfocitos T con fines de inmunoterapia. (Texto tomado de la fuente)Adoptive cell therapy has the potential to increase antitumor immunity by modifying cells in-vitro to expand lymphocytes that recognize and attack the tumor. The functional capacity and survival of the cells transferred to the patient heavily depends on the memory subpopulations that are being expanded in the laboratory, hence, obtaining early memory cells is desirable. The main objective of our work was to determine a strategy for in-vitro expansion of human stem cell-like memory T CD4 lymphocytes. Starting from naive cells, stimulated with a polyclonal agent supplemented with different combinations of cytokines from the common gamma family, we found that the combination of IL-7, IL-15 and IL-21 or IL-7 and IL-21 were the cocktails that produced a greater number of cells with a stem memory phenotype, measured by flow cytometry. Additionally, through the measurement of membrane proteins and in-silico analysis, a close relationship between stem cell-like memory and the follicular helper T cells differentiation program was established, which we believe contributes to a better understanding of the processes that underlie the generation and maintenance of memory and, therefore, may improve current strategies of expansion of T cells for immunotherapy purposes.MaestríaMagíster en InmunologíaMedicina Traslacional154 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Maestría en InmunologíaFacultad de MedicinaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y saludLinfocitos TTécnicas In VitroT-LymphocytesIn Vitro TechniquesTerapia adoptiva de célulasMemoriaLinfocitos T CD4VacunaciónLinfocitos T foliculares helperAdoptive cell therapyMemoryCD4 T lymphocytesVaccinationHelper Follicular T LymphocytesDeterminación de condiciones in-vitro para la expansión de células T Stem de memoria para terapia adoptiva de célulasDetermination of in-vitro conditions to expand stem memory T Cells for adoptive cell therapyTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMRedColLaReferenciaPerica K, Varela JC, Oelke M, Schneck J. Adoptive T cell immunotherapy for cancer. Rambam Maimonides medical journal. 2015;6(1):e0004.Rohaan MW, Wilgenhof S, Haanen J. Adoptive cellular therapies: the current landscape. Virchows Archiv : an international journal of pathology. 2019;474(4):449-61.Kondo T, Imura Y, Chikuma S, Hibino S, Omata-Mise S, Ando M, et al. Generation and application of human induced-stem cell memory T cells for adoptive immunotherapy. Cancer science. 2018;109(7):2130-40.Esfahani K, Roudaia L, Buhlaiga N, Del Rincon SV, Papneja N, Miller WH, Jr. A review of cancer immunotherapy: from the past, to the present, to the future. Current oncology. 2020;27(Suppl 2):S87-S97.Morotti M, Albukhari A, Alsaadi A, Artibani M, Brenton JD, Curbishley SM, et al. Promises and challenges of adoptive T-cell therapies for solid tumours. British journal of cancer. 2021;124(11):1759-76.Dafni U, Michielin O, Lluesma SM, Tsourti Z, Polydoropoulou V, Karlis D, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Annals of oncology : official journal of the European Society for Medical Oncology. 2019;30(12):1902-13.June CH. Adoptive T cell therapy for cancer in the clinic. The Journal of clinical investigation. 2007;117(6):1466-76.Met O, Jensen KM, Chamberlain CA, Donia M, Svane IM. Principles of adoptive T cell therapy in cancer. Seminars in immunopathology. 2019;41(1):49-58.Crompton JG, Sukumar M, Restifo NP. Uncoupling T-cell expansion from effector differentiation in cell-based immunotherapy. Immunological reviews. 2014;257(1):264-76.Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. The Journal of clinical investigation. 2005;115(6):1616-26.Spolski R, Gromer D, Leonard WJ. The gamma c family of cytokines: fine-tuning signals from IL-2 and IL-21 in the regulation of the immune response. F1000Research. 2017;6:1872.Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2013;121(4):573-84.Pietrobon V, Todd LA, Goswami A, Stefanson O, Yang Z, Marincola F. Improving CAR T-Cell Persistence. International journal of molecular sciences. 2021;22(19).Hegde PS, Chen DS. Top 10 Challenges in Cancer Immunotherapy. Immunity. 2020;52(1):17-35.Taefehshokr S, Parhizkar A, Hayati S, Mousapour M, Mahmoudpour A, Eleid L, et al. Cancer immunotherapy: Challenges and limitations. Pathology, research and practice. 2022;229:153723.Arcangeli S, Falcone L, Camisa B, De Girardi F, Biondi M, Giglio F, et al. Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients. Frontiers in immunology. 2020;11:1217.Majzner RG, Mackall CL. Clinical lessons learned from the first leg of the CAR T cell journey. Nature medicine. 2019;25(9):1341-55.Li Y, Wu D, Yang X, Zhou S. Immunotherapeutic Potential of T Memory Stem Cells. Frontiers in oncology. 2021;11:723888.Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nature reviews Immunology. 2002;2(4):251-62.Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348(6230):62-8.Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233(4770):1318-21.Belldegrun A, Muul LM, Rosenberg SA. Interleukin 2 expanded tumor-infiltrating lymphocytes in human renal cell cancer: isolation, characterization, and antitumor activity. Cancer research. 1988;48(1):206-14.Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(32):5233-9.Busch DH, Frassle SP, Sommermeyer D, Buchholz VR, Riddell SR. Role of memory T cell subsets for adoptive immunotherapy. Seminars in immunology. 2016;28(1):28-34.Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708-12.Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. Journal of immunology. 1993;150(3):1122-36.Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature medicine. 2009;15(7):808-13.Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al. A human memory T cell subset with stem cell-like properties. Nature medicine. 2011;17(10):1290-7.Kwok WW, Tan V, Gillette L, Littell CT, Soltis MA, LaFond RB, et al. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. Journal of immunology. 2012;188(6):2537-44.Gattinoni L, Speiser DE, Lichterfeld M, Bonini C. T memory stem cells in health and disease. Nature medicine. 2017;23(1):18-27.Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001;291(5512):2413-7.Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who's who of T-cell differentiation: human memory T-cell subsets. European journal of immunology. 2013;43(11):2797-809.Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nature immunology. 2003;4(3):225-34.Ahmed R, Bevan MJ, Reiner SL, Fearon DT. The precursors of memory: models and controversies. Nature reviews Immunology. 2009;9(9):662-8.Gasper DJ, Tejera MM, Suresh M. CD4 T-cell memory generation and maintenance. Critical reviews in immunology. 2014;34(2):121-46.Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? Journal of immunotherapy. 2012;35(9):651-60.Joshi NS, Kaech SM. Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. Journal of immunology. 2008;180(3):1309-15.Lanzavecchia A, Sallusto F. Progressive differentiation and selection of the fittest in the immune response. Nature reviews Immunology. 2002;2(12):982-7.Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science. 2007;315(5819):1687-91.Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nature reviews Cancer. 2012;12(10):671-84.Simons BD, Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell. 2011;145(6):851-62.Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nature reviews Immunology. 2009;9(7):480-90.Jicha DL, Mule JJ, Rosenberg SA. Interleukin 7 generates antitumor cytotoxic T lymphocytes against murine sarcomas with efficacy in cellular adoptive immunotherapy. The Journal of experimental medicine. 1991;174(6):1511-5.Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636-45.Toe JG, Pellegrini M, Mak TW. Promoting immunity during chronic infection--the therapeutic potential of common gamma-chain cytokines. Molecular immunology. 2013;56(1-2):38-47.Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995;2(4):331-9.Rathmell JC, Farkash EA, Gao W, Thompson CB. IL-7 enhances the survival and maintains the size of naive T cells. Journal of immunology. 2001;167(12):6869-76.Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature reviews Immunology. 2006;6(8):595-601.Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. Journal of immunology. 2005;175(12):7867-79.Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. Journal of immunology. 2004;173(9):5361-71.Chen Y, Yu F, Jiang Y, Chen J, Wu K, Chen X, et al. Adoptive Transfer of Interleukin-21-stimulated Human CD8+ T Memory Stem Cells Efficiently Inhibits Tumor Growth. Journal of immunotherapy. 2018;41(6):274-83.Alvarez-Fernandez C, Escriba-Garcia L, Vidal S, Sierra J, Briones J. A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy. Journal of translational medicine. 2016;14(1):214.Nakayamada S, Takahashi H, Kanno Y, O'Shea JJ. Helper T cell diversity and plasticity. Current opinion in immunology. 2012;24(3):297-302.Pepper M, Pagan AJ, Igyarto BZ, Taylor JJ, Jenkins MK. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity. 2011;35(4):583-95.Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nature immunology. 2011;12(6):467-71.He J, Tsai LM, Leong YA, Hu X, Ma CS, Chevalier N, et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity. 2013;39(4):770-81.Vinuesa CG, Linterman MA, Yu D, MacLennan IC. Follicular Helper T Cells. Annual review of immunology. 2016;34:335-68.Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. The Journal of experimental medicine. 2000;192(11):1545-52.Bowen MB, Butch AW, Parvin CA, Levine A, Nahm MH. Germinal center T cells are distinct helper-inducer T cells. Human immunology. 1991;31(1):67-75.Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000;406(6793):309-14.Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 1996;87(6):1037-47.Walker LS, Gulbranson-Judge A, Flynn S, Brocker T, Raykundalia C, Goodall M, et al. Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers. The Journal of experimental medicine. 1999;190(8):1115-22.King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annual review of immunology. 2008;26:741-66.Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, et al. Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39(4):758-69.Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annual review of immunology. 2008;26:677-704.Jeza VT, Li X, Chen J, Liang Z, Aggrey AO, Wu X. IL-21 Augments Rapamycin in Expansion of Alpha Fetoprotein Antigen Specific Stem-Cell-like Memory T Cells in vitro. The Pan African medical journal. 2017;27:163.Mueller SN, Gebhardt T, Carbone FR, Heath WR. Memory T cell subsets, migration patterns, and tissue residence. Annual review of immunology. 2013;31:137-61.Olenchock BA, Rathmell JC, Vander Heiden MG. Biochemical Underpinnings of Immune Cell Metabolic Phenotypes. Immunity. 2017;46(5):703-13.Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38(4):633-43.Buck MD, O'Sullivan D, Pearce EL. T cell metabolism drives immunity. The Journal of experimental medicine. 2015;212(9):1345-60.Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013;38(2):225-36.Araujo L, Khim P, Mkhikian H, Mortales CL, Demetriou M. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife. 2017;6.Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342(6155):1242454.O'Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD, et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014;41(1):75-88.van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.Vella LA, Buggert M, Manne S, Herati RS, Sayin I, Kuri-Cervantes L, et al. T follicular helper cells in human efferent lymph retain lymphoid characteristics. The Journal of clinical investigation. 2019;129(8):3185-200.Kared H, Tan SW, Lau MC, Chevrier M, Tan C, How W, et al. Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway. Nature communications. 2020;11(1):821.Bai J, Gao Z, Li X, Dong L, Han W, Nie J. Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget. 2017;8(66):110693-707.Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. International immunology. 1996;8(5):765-72.Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, et al. Expression of programmed death 1 ligands by murine T cells and APC. Journal of immunology. 2002;169(10):5538-45.DiPiazza A, Richards KA, Knowlden ZA, Nayak JL, Sant AJ. The Role of CD4 T Cell Memory in Generating Protective Immunity to Novel and Potentially Pandemic Strains of Influenza. Frontiers in immunology. 2016;7:10.Spolski R, Leonard WJ. Interleukin-21: a double-edged sword with therapeutic potential. Nature reviews Drug discovery. 2014;13(5):379-95.Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408(6808):57-63.Bugya Z, Prechl J, Szenasi T, Nemes E, Bacsi A, Koncz G. Multiple Levels of Immunological Memory and Their Association with Vaccination. Vaccines. 2021;9(2).Fuertes Marraco SA, Soneson C, Cagnon L, Gannon PO, Allard M, Abed Maillard S, et al. Long-lasting stem cell-like memory CD8+ T cells with a naive-like profile upon yellow fever vaccination. Science translational medicine. 2015;7(282):282ra48.da Silva Antunes R, Paul S, Sidney J, Weiskopf D, Dan JM, Phillips E, et al. Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses. PloS one. 2017;12(1):e0169086.Mayer S, Laumer M, Mackensen A, Andreesen R, Krause SW. Analysis of the immune response against tetanus toxoid: enumeration of specific T helper cells by the Elispot assay. Immunobiology. 2002;205(3):282-9.Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immunity & ageing : I & A. 2019;16:25.Pereira B, Xu XN, Akbar AN. Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly. Frontiers in immunology. 2020;11:583019.Rodriguez IJ, Lalinde Ruiz N, Llano Leon M, Martinez Enriquez L, Montilla Velasquez MDP, Ortiz Aguirre JP, et al. Immunosenescence Study of T Cells: A Systematic Review. Frontiers in immunology. 2020;11:604591.Bruggner RV, Bodenmiller B, Dill DL, Tibshirani RJ, Nolan GP. Automated identification of stratifying signatures in cellular subpopulations. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(26):E2770-7.Ding ZC, Shi H, Aboelella NS, Fesenkova K, Park EJ, Liu Z, et al. Persistent STAT5 activation reprograms the epigenetic landscape in CD4(+) T cells to drive polyfunctionality and antitumor immunity. Science immunology. 2020;5(52).Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325(5943):1006-10.Martinez GJ, Hu JK, Pereira RM, Crampton JS, Togher S, Bild N, et al. Cutting Edge: NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection. Journal of immunology. 2016;196(5):2015-9.Salerno F, Turner M, Wolkers MC. Dynamic Post-Transcriptional Events Governing CD8(+) T Cell Homeostasis and Effector Function. Trends in immunology. 2020;41(3):240-54.Tough DF, Rioja I, Modis LK, Prinjha RK. Epigenetic Regulation of T Cell Memory: Recalling Therapeutic Implications. Trends in immunology. 2020;41(1):29-45.Corrado M, Pearce EL. Targeting memory T cell metabolism to improve immunity. The Journal of clinical investigation. 2022;132(1).Li W, Zhang L. Rewiring Mitochondrial Metabolism for CD8(+) T Cell Memory Formation and Effective Cancer Immunotherapy. Frontiers in immunology. 2020;11:1834.Zorova LD, Popkov VA, Plotnikov EY, Silachev DN, Pevzner IB, Jankauskas SS, et al. Mitochondrial membrane potential. Analytical biochemistry. 2018;552:50-9.McKinstry KK, Strutt TM, Swain SL. Regulation of CD4+ T-cell contraction during pathogen challenge. Immunological reviews. 2010;236:110-24.Zhan Y, Carrington EM, Zhang Y, Heinzel S, Lew AM. Life and Death of Activated T Cells: How Are They Different from Naive T Cells? Frontiers in immunology. 2017;8:1809.Jameson SC, Masopust D. Understanding Subset Diversity in T Cell Memory. Immunity. 2018;48(2):214-26.Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation. The Journal of experimental medicine. 2012;209(2):243-50.Lalinde-Ruiz N, Rodriguez IJ, Bernal-Estevez DA, Parra-Lopez CA. Young but not older adults exhibit an expansion of CD45RA(+)CCR7(+)CD95(+) T follicular helper cells in response to tetanus vaccine. Experimental gerontology. 2021;156:111599.Rovini A, Heslop K, Hunt EG, Morris ME, Fang D, Gooz M, et al. Quantitative analysis of mitochondrial membrane potential heterogeneity in unsynchronized and synchronized cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2021;35(1):e21148.Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. Journal of immunology. 2008;181(7):4832-9.Quintelier K, Couckuyt A, Emmaneel A, Aerts J, Saeys Y, Van Gassen S. Analyzing high-dimensional cytometry data using FlowSOM. Nature protocols. 2021;16(8):3775-801.Schmitt N, Bentebibel SE, Ueno H. Phenotype and functions of memory Tfh cells in human blood. Trends in immunology. 2014;35(9):436-42.Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nature reviews Immunology. 2016;16(2):102-11.EstudiantesInvestigadoresMaestrosLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/82620/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1018467284. 2022.pdf1018467284. 2022.pdfTesis de Maestría en Inmunologíaapplication/pdf8801257https://repositorio.unal.edu.co/bitstream/unal/82620/2/1018467284.%202022.pdfe57e5f9a2c15d51ec02b55cd479ee261MD52THUMBNAIL1018467284. 2022.pdf.jpg1018467284. 2022.pdf.jpgGenerated Thumbnailimage/jpeg4336https://repositorio.unal.edu.co/bitstream/unal/82620/3/1018467284.%202022.pdf.jpgf881abafb882fb5ba47a4fb771279669MD53unal/82620oai:repositorio.unal.edu.co:unal/826202024-08-12 23:11:25.89Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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

Publicaciones similares