Differentiation and functions of CD4+ effector T cells
DOI:
https://doi.org/10.33910/2687-1270-2025-6-3-239-251Keywords:
genes, interleukins, T lymphocytes, transcription factors, receptors, chemokines, homozygous mutationsAbstract
This review describes the subpopulations of effector CD4+ T lymphocytes — including Th1, Th2, Th17, Th9, Th22, and follicular helper T (Tfh) cells — their biological characteristics, and the roles of key transcription factors and signaling pathways in their maturation and differentiation. The review also summarizes the principal interleukins secreted by these effector subsets and their roles in generating an anti-infective immune response, as well as their potential contribution to immunopathology. Furthermore, the article describes the adhesion molecules and humoral factors that mediate the precise cellular interactions required for the maturation and differentiation of CD4+ T lymphocyte populations. The effector CD4+ T lymphocyte population is primarily composed of three major helper subsets: Th1, Th2, and Th17 cells, each defined by distinct cytokine secretion profiles. Th1 cells recognize antigens derived from intracellular microbes and activate phagocytes to destroy these pathogens. Macrophage activation by Th1 cells is mediated through interactions involving IFNγ and the CD40L–CD40 signaling axis. Thl cells are critical in the development of hereditary immunodeficiencies, involving homozygous mutations in the receptors for IFNγ, IL-12, and STAT1. Th2 cells respond to antigens expressed by extracellular parasitic microbes and allergens. Their maturation and differentiation are promoted by the cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Thl7 cells stimulate neutrophil activation to eliminate extracellular bacteria and fungi and maintain the integrity of the epithelium. Th17 cells may also play a crucial role in preventing tissue damage in autoimmune diseases. Key signaling molecules and pathways that govern T lymphocyte maturation and differentiation include JAK-3, STAT1-6, T_T-BET, and GATA-3. Dysregulation of these molecules is associated with functional impairments in Th1 and Th2 cells.
References
Baumjohann, D., Ansel, K. M. (2013) MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nature Reviews Immunology, vol. 13, no. 9, pp. 666–678. https://doi.org/10.1038/nri3494 (In English)
Cua, D. J., Sherlock, J., Chen, Y. et al. (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature, vol. 421, no. 6924, pp. 744–748. https://doi.org/10.1038/nature01355 (In English)
Godfrey, D. I., Uldrich, A. P., McCluskey, J. et al. (2015) The burgeoning family of unconventional T cells. Nature Immunology, vol. 16, no. 11, pp. 1114–1123. https://doi.org/10.1038/ni.3298 (In English)
Ivanov, N., McKenzie, B. S., Zhou, L. et al. (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell, vol. 126, no. 6, pp. 1121–1133. https://doi.org/10.1016/j.cell.2006.07.035 (In English)
Ivashkiv, L. B. (2018) IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nature Reviews Immunology, vol. 18, no. 9, pp. 545–558. https://doi.org/10.1038/s41577-018-0029-z (In English)
Kanno, Y., Vahedi, G., Hirahara, K. et al. (2012) Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annual Review of Immunology, vol. 30, pp. 707– 731. https://doi.org/10.1146/annurev-immunol-020711-075058 (In English)
Mackaness, G. B. (1962) Cellular resistance to infection. Journal of Experimental Medicine, vol. 116, no. 3, pp. 381–406. https://doi.org/10.1084/jem.116.3.381 (In English)
Mazzoni, A., Maggi, L., Liotta, F. et al. (2019) Biological and clinical significance of T helper 17 cell plasticity. Immunology, vol. 158, no. 4, pp. 287–295. https://doi.org/10.1111/imm.13124 (In English)
McGeachy, M. J., Cua, D. J., Gaffen, S. L. (2019) The IL-17 family of cytokines in health and disease. Immunity, vol. 50, no. 4, pp. 892–906. https://doi.org/10.1016/j.immuni.2019.03.021 (In English)
Mori, L., Lepore, M., De Libero, G. (2016) The immunology of CD1- and MR1-restricted T cells. Annual Review of Immunology, vol. 34, pp. 479–510. https://doi.org/10.1146/annurev-immunol-032414-112008 (In English)
Moskalev, A. V., Apchel, V. Ya., Nikitina, E. A. (2024) Sovremennye aspekty organizatsii molekul glavnogo kompleksa gistosovmestimosti i osobennosti razvitiya immunnogo otveta [Modern aspects of the organization of molecules of the main histocompatibility complex and the development of the immune response]. Integrativnaya fiziologiya — Integrative Physiology, vol. 5, no. 3, pp. 261–282. https://doi.org/10.33910/2687-1270-2024-5-3-261-282 (in Russian)
Moskalev, A. V., Gumilyevsky, B. Yu., Apchel, V. Ya., Tsygan, V. N. (2019) T-limfotsity — “tsenzornye” kletki immunnoj sistemy [T-lymphocytes are “censored” cells of the immune system]. Vestnik Rossiyskoy Voenno-meditsinskoy akademii — Bulletin of the Russian Military Medical Academy, vol. 21, no. 2, pp. 191–197. https://doi.org/10.17816/brmma25943 (in Russian)
Moskalev, A. V., Gumilyevsky, B. Yu., Apchel, V. Ya., Tsygan, V. N. (2022a) Kletochnye i gumoralnye factory vrozhdennogo protivovirusnogo immuniteta [Cellular and humoral factors of innate antiviral immunity]. Vestnik Rossiyskoy Voenno-meditsinskoy akademii — Bulletin of the Russian Military Medical Academy, vol. 24, no. 4, pp. 751–764. https://doi.org/10.17816/brmma108136 (in Russian)
Moskalev, A. V., Gumilevsky, B. Yu., Apchel, V. Ya., Tsygan, V. N. (2022b) Osobennosti rasvitiya adaptivnogo protivovirusnogo immunnogo otveta [Features of the development of an adaptive antiviral immune response]. Vestnik Rossiyskoy Voenno-meditsinskoy akademii — Bulletin of the Russian Military Medical Academy, vol. 24, no. 4, pp. 789–800. https://doi.org/10.17816/brmma109497 (in Russian)
Mosmann, T. R., Cherwinski, H., Bond, M. W. et al. (1986) Two types of murine helper T cell done. I. Definition according to profiles of lymphokine activities and secreted proteins. The Journal of Immunology, vol. 136, no. 7, pp. 2348–2357. (In English)
Murphy, K. M., Stockinger, B. (2010) Effector T cell plasticity: Flexibility in the face of changing circumstances. Nature Immunology, vol. 11, no. 8, pp. 674–680. https://doi.org/10.1038/ni.1899 (In English)
Nakayama, T., Hirahara, K., Onodera, A. et al. (2017) Th2 cells in health and disease. Annual Review of Immunology, vol. 35, pp. 53–84. https://doi.org/10.1146/annurev-immunol-051116-052350 (In English)
Nielsen, M. M., Witherden, D. A., Havran, W. L. (2017) γδ T cells in homeostasis and host defence of epithelial barrier tissues. Nature Reviews Immunology, vol. 17, no. 12, pp. 733–745. https://doi.org/10.1038/nri.2017.101 (In English)
Patel, D. D., Kuchroo, V. K. (2015) Thl7 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity, vol. 43, no. 6, pp. 1040–1051. https://doi.org/10.1016/j.immuni.2015.12.003 (In English)
Pritchard, G. H., Kedl, R. M., Hunter, C. A. (2019) The evolving role of T-bet in resistance to infection. Nature Reviews Immunology, vol. 19, no. 6, pp. 398–410. https://doi.org/10.1038/s41577-019-0145-4 (In English)
Provine, N. M., Klenerman, P. (2020) MAIT cells in health and disease. Annual Review of Immunology, vol. 38, pp. 203–228. https://doi.org/10.1146/annurev-immunol-080719-015428 (In English)
Pulendran, B., Artis, D. (2012) New paradigms in type 2 immunity. Science, vol. 337, no. 6093, pp. 431–435. https://doi.org/10.1126/science.1221064 (In English)
Sallusto, F. (2016) Heterogeneity of human CD4+ T cells against microbes. Annual Review of Immunology, vol. 34, pp. 317–334. https://doi.org/10.1146/annurev-immunol-032414-112056 (In English)
Schmitt, N., Ueno, H. (2015) Regulation of human helper T cell subset differentiation by cytokines. Current Opinion in Immunology, vol. 34, pp. 130–136. https://doi.org/10.1016/j.coi.2015.03.007 (In English)
Schorer, M., Kuchroo, V. K., Joller, N. (2019) Role of Co-stimulatory mol–ecules in T helper cell differentiation. In: M. Azuma, H. Yagita (eds.). Co-signal Molecules in T Cell Activation. Advances in Experimental Medicine and Biology. Vol. 1189. Singapore: Springer Publ., pp. 153–177. https://doi.org/10.1007/978-981-32-9717-3_6 (In English)
Sica, A., Mantovani, A. (2012) Macrophage plasticity and polarization: in vivo veritas. Journal of Clinical Investigation, vol. 122, no. 3, pp. 787–795. https://doi.org/10.1172/JCI59643 (In English)
Stockinger, B., Omenetti, S. (2017) The dichotomous nature of T helper 17 cells. Nature Reviews Immunology, vol. 17, no. 9, pp. 535–544. https://doi.org/10.1038/nri.2017.50 (In English)
Sungnak, W., Wang, C., Kuchroo, V. K. (2019) Multilayer regulation of CD4 T cell subset differentiation in the era of single cell genomics. Advances in Immunology, vol. 141, pp. 1–31. https://doi.org/10.1016/bs.ai.2018.12.001 (In English)
Szabo, S. J., Kim, S. T., Costa, G. L. et al. (2000) A novel transcription factor, T-bet, directs Thl lineage commitment. Cell, vol. 100, no. 6, pp. 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3 (In English)
Tubo, N. J., Jenkins, M. K. (2014) TCR signal quantity and quality in CD4+ T cell differentiation. Trends in Immunology, vol. 35, no. 12, pp. 591–596. https://doi.org/10.1016/j.it.2014.09.008 (In English)
Van Dyken, S. J., Locksley, R. M. (2013) Interleukin-4 and interleukin-13 — mediated alternatively activated macrophages: Roles in homeostasis and disease. Annual Review of Immunology, vol. 31, pp. 317–343. https://doi.org/10.1146/annurev-immunol-032712-095906 (In English)
Walker, J. A., McKenzie, A. N. J. (2018) TH2 cell development and function. Nature Reviews Immunology, vol. 18, no. 2, pp. 121–133. https://doi.org/10.1038/nri.2017.118 (In English)
Wynn, T. A. (2015) Type 2 cytokines: Mechanisms and therapeutic strategies. Nature Reviews Immunology, vol. 15, no. 5, pp. 271–282. https://doi.org/10.1038/nri3831 (In English)
Wynn, T. A., Chawla, A., Pollard, J. W. (2013) Macrophage biology in development, homeostasis and disease. Nature, vol. 496, no. 7446, pp. 445–455. https://doi.org/10.1038/nature12034 (In English)
Zheng, W., Flavell, R. A. (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell, vol. 89, no. 4, pp. 587–596. https://doi.org/10.1016/s0092-8674(00)80240-8 (In English)
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