T-helper subpopulations and their biological effects

The biological features of a subpopulation of T helper cells: Th1, Th2, Th17, Th9, Th22, follicular T lymphocytes are considered. The corresponding transcription factors, signaling pathways involved in the biological effects of CD4+T lymphocytes, and interleukins secreted by them, which influence the development of the immune response, are characterized. The maturation efficiency and differentiation of T-helper cells depend on adhesion molecules and humoral factors. Thl-type are critically important in the development of primary immunodeficiency states, homozygous mutations associated with IFN-γ, IL-12 receptors, and STAT1 signaling proteins. IL-25, IL-33, and thymus stromal lymphopoietin are involved in the biological activation of Th2-type. JAK-3, STAT1-6, T_T-BET, and GATA-3 are involved in the maturation and differentiation of T-lymphocytes. Deviations in the functioning of these molecules lead to changes in the biological effects of Th1-type and Th2-type. Thus, the biological effects of the T-helper subpopulation are of great importance in the implementation of innate and acquired immune responses, and new research in this area is certainly relevant.

1. Moskalev A. V., Gumilevskii B. Yu., Apchel A. V., Tsygan V. N. T-lymphocytes – “censor” cells of the immune system. Vestnik Rossiiskoy voenno-meditsinskoy akademii = Bulletin of the Russian Military Medical Academy. 2019; 2 (66): 191–197. doi: 10.17816/brmma25943 (In Russ.).

2. Moskalev A. V., Gumilevskii B. Yu., Apchel V. Ya., Tsygan V. N. Cellular and humoral factors of innate antiviral immunity. Vestnik Rossiiskoy voenno-meditsinskoy akademii = Bulletin of the Russian Military Medical Academy. 2022; 24 (4): 751–764. doi: 10.17816/brmma108136 (In Russ.).

3. Moskalev A. V., Gumilevskii B. Yu., Apchel V. Ya., Tsygan V. N. Features of the development of adaptive antiviral immune response. Vestnik Rossiiskoy voenno-meditsinskoy akademii = Bulletin of the Russian Military Medical Academy. 2022; 24 (4): 789–800. doi: 10.17816/brmma109497 (In Russ.).

4. Baumjohann D., Ansel K. M. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nature Reviews Immunology. 2013; 13: 666–678. doi: 10.1038/nri3494.

5. Murphy K. M., Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nature Immunology. 2010; 11: 674–680. doi: 10.1038/ni.1899.

6. Mackaness G. B. Cellular resistance to infection. Journal of Experimental Medicine. 1962; 116: 381–406. doi: 10.1084/jem.116.3.381.

7. Mosmann T. R., Cherwinski H., Bond M. W. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology. 1986; 136: 2348–2357. doi: 10.1016/j.immuni.2019.03.021.

8. Nakayama T., Hirahara K., Onodera A. Th2 cells in health and disease. Annual Review of Immunology. 2017; 35: 53–84. doi: 10.1146/annurev-immunol-051116-052350.

9. Pritchard G. H., Kedl R. M., Hunter C. A. The evolving role of T-bet in resistance to infection. Nature Reviews Immunology. 2019; 19: 398–410. doi: 10.1016/j.immuni.2015.12.003.

10. Kanno Y., Vahedi G., Hirahara K. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annual Review of Immunology. 2012; 30: 707–731. doi: 10.1146/annurev-immunol-020711-075058.

11. Mazzoni A., Maggi L., Liotta F. Biological and clinical significance of T helper 17 cell plasticity. Immunology. 2019; 158: 287–295. doi: 10.1111/imm.13124.

12. Patel D. D., Kuchroo V. K. Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity. 2015; 43: 1040–1051. doi: 10.1016/j.immuni.2015.12.003.

13. Pulendran B., Artis D. New paradigms in type 2 immunity. Science. 2012; 337: 431–435. doi: 10.1126/science.1221064.

14. Ivashkiv L. B. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nature Reviews Immunology. 2018; 18: 545–558. doi: 10.1038/s41577-018-0029-z.

15. Sallusto F. Heterogeneity of human CD4(+) T cells against microbes. Annual Review of Immunology. 2016; 34: 317–334. doi: 10.1146/annurev-immunol-051116-052350.

16. Schmitt N., Ueno H. Regulation of human helper T cell subset differentiation by cytokines. Current Opinion in Immunology. 2015; 34: 130–136. doi: 10.1016/j.coi.2015.03.007.

17. Sungnak W., Wang C., Kuchroo V. K. Multilayer regulation of CD4 T cell subset differentiation in the era of single cell genomics. Advances in Immunology. 2019; 141: 1–31. doi: 10.1016/bs.ai.2018.12.001.

18. Tubo N. J., Jenkins M. K. TCR signal quantity and quality in CD4+ T cell differentiation. Trends in Immunology. 2014; 35: 591–596. doi: 10.1016/j.it.2014.09.008.

19. Vantourout P., Hayday A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nature Reviews Immunology. 2013; 13: 88–100. doi: 10.1038/nri3384.

20. Walker J. A., McKenzie A. N. J. TH2 cell development and function. Nature Reviews Immunology. 2018; 18: 121–133. doi: 10.1038/nri.2017.118.

21. Wynn T. A. Type 2 cytokines: mechanisms and therapeutic strategies. Nature Reviews Immunology. 2015; 15: 271–282. doi: 10.1038/nri3831.

22. Wynn T. A., Chawla A., Pollard J. W. Macrophage biology in development, homeostasis and disease. Nature. 2013; 496: 445–455. doi: 10.1038/nature12034.

23. Sica A., Mantovani A. Macrophage plasticity and polarization: in vivo veritas. Journal of Clinical Investigation. 2012; 122: 787–795. doi: 10.1172/JCI59649.

24. Szabo S. J., Kim S. T., Costa G. L. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000; 100: 655–669. doi: 10.1016/S0092-8674(00)80702-3.

25. Zheng W., Flavell R. A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997; 89: 587–596. doi: 10.1016/S0092-8674(00)80240-8.

26. Schorer M., Kuchroo V. K., Joller N. Role of co-stimulatory molecules in T helper cell differentiation. Advances in Experimental Medicine and Biology. 2019; 1189: 153–177. doi: 10.1007/978-3-030-30583-9_8.

27. Van Dyken S. J., Locksley R. M. Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu. Rev. Immunol. 2013; 31: 317–343. doi: 10.1146/annurev-immunol-032712-095906.

28. Cua D. J., Sherlock J., Chen Y. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003; 421: 744–748. doi: 10.1038/nature01396.

29. Ivanov I. I., McKenzie B. S., Zhou L. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006; 126: 1121–1133. doi: 10.1016/j.cell.2006.07.035.

30. McGeachy M. J., Cua D. J., Gaffen S. L. The IL-17 family of cytokines in health and disease. Immunity. 2019; 50: 892–906. doi: 10.1016/j.immuni.2019.03.021.

31. Stockinger B., Omenetti S. The dichotomous nature of T helper 17 cells. Nature Reviews Immunology. 2017; 17: 535–544. doi: 10.1038/nri.2017.50.

32. Nielsen M. M., Witherden D. A., Havran W. L. γδ T cells in homeostasis and host defence of epithelial barrier tissues. Nature Reviews Immunology. 2017; 17: 733–745. doi: 10.1038/nri.2017.101.

33. Godfrey D. I., Uldrich A. P., McCluskey J. The burgeoning family of unconventional T cells. Nature Immunology. 2015; 16: 1114–1123. doi: 10.1038/ni.3298.

34. Provine N. M., Klenerman P. MAIT cells in health and disease. Annual Review of Immunology. 2020; 38: 203–228. doi: 10.1146/annurev-immunol-080719-015428.

35. Mori L., Lepore M., De Libero G. The immunology of CD1- and MR1-restricted T cells. Annual Review of Immunology. 2016; 34: 479–510. doi: 10.1146/annurev-immunol-032414-112008.