References

mimmun

Медицинская иммунология

Medical Immunology (Russia)

1563-06252313-741X

SPb RAACI

mimmun-3509

Research Article

ОБЗОРЫ

REVIEWS

Т-регуляторные клетки: многоликие и вездесущие

Regulatory T cells: multifaceted and omnipresent

https://orcid.org/0009-0008-8631-0339

Ризопулу

А. П.

Rizopulu

Anna P.

доктор биологических наук, доцент кафедры клинической лабораторной диагностики с курсом лабораторной иммунологии

PhD, MD (Biology), Associate Professor, Department of Clinical Laboratory Diagnostics with a Course in Laboratory Immunology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russia

annarizopulu@inbox.ru

https://orcid.org/0000-0003-3749-1950

Гариб

Фируз Юсупович

Garib

Firuz Yu.

доктор медицинских наук, профессор, профессор кафедр иммунологии

PhD, MD (Medicine), Professor, Professor, Department of Clinical Laboratory Diagnostics with a Course in Laboratory Immunology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation; Professor, Department of Immunology, Lomonosov Moscow State University; Professor, Department of Immunology, Sechenov University, Moscow, Russia

fgarib@yandex.ru

https://orcid.org/0000-0003-3855-217X

Гариб

Виктория Фирузовна

Garib

Viktorya F.

доктор медицинских наук, профессор, консультант Международного центра молекулярной аллергологии

PhD, MD (Medicine), Professor, consultant of the International Center for Molecular Allergology of the Academy of Sciences of the Republic of Uzbekistan, Tashkent, Republic of Uzbekistan

vgarib@inbox.ru

Российская медицинская академия непрерывного профессионального образованияРоссияRussian Medical Academy of Continuous Professional Education, Moscow, Russian FederationRussian Federation

Российская медицинская академия непрерывного последипломного образованияРоссияRussian Medical Academy of Continuous Professional Education, Moscow, Russian Federation; Lomonosov Moscow State University, Moscow, Russian Federation; Sechenov University, Moscow, Russian FederationRussian Federation

Международный центр молекулярной аллергологииУзбекистанInternational Center of Molecular Allergology of Academy of Science, Tashkent, UzbekistanUzbekistan

2019

16102026

Online First

3509

2019

Ризопулу А.П., Гариб Ф.Ю., Гариб В.Ф.

Rizopulu A.P., Garib F.Y., Garib V.F.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.mimmun.ru/mimmun/article/view/3509

Резюме. Т‑регуляторные клетки (Treg) — ключевые медиаторы иммунной толерантности и тканевого гомеостаза, предотвращающие аутоиммунные реакции и избыточное воспаление. Основные субпопуляции: тимические (tTreg/nTreg), формирующиеся в тимусе и обогащённые рецепторами к аутоантигенам; индуцированные (iTreg/pTreg), дифференцирующиеся на периферии из наивных CD4⁺ T‑клеток. Фенотипическая идентификация базируется на экспрессии Foxp3, CD25 и низком уровне CD127. Механизмы супрессии включают: секрецию ингибиторных цитокинов (IL‑10, TGF‑β, IL‑35); действие молекул контрольных точек (CTLA‑4, PD‑1, LAG‑3, TIGIT); метаболическую модуляцию через CD39/CD73 (генерация аденозина); подавление Ca²⁺‑сигнализации в эффекторных лимфоцитах и др. Стабильность Treg поддерживается эпигенетическими механизмами и метаболическими программами; пластичность проявляется в формировании гибридных субпопуляций Treg/Th c частичной супрессорной активностью и продукцией соответствующих цитокинов хелперной составляющей: Th1-Treg, Th2-Treg, Th17-Treg, Tfr-Treg — в зависимости от тканевого микроокружения [35]. Миграция и тканевая резидентность регулируются хемокиновыми рецепторами и молекулами адгезии. CD69 блокирует S1PR1, обеспечивая удержание Treg в ткани. ST2 служит маркером и функциональным рецептором Treg в барьерных тканях и активируется «сигналами тревоги» (IL‑33). В разных органах Treg приобретают уникальный транскриптом и функциональные особенности (например, в кишечнике — α4β7⁺CD103⁺, в жировой ткани — зависимость от PPARγ, ID2, BATF), участвуют в поддержании толерантности, контроле воспаления и индукции репаративных процессов путем подавления воспаления и переключения макрофагов на М2 фенотип. Treg обеспечивают протективный контроль иммунного ответа, но в ряде случаев (опухоли, фиброз) могут способствовать прогрессированию заболевания. Изучение стабильности, пластичности и миграции Treg открывает перспективы для таргетной иммунотерапии.

Abstract. Regulatory T cells (Treg) are key mediators of immune tolerance and tissue homeostasis, preventing autoimmune reactions and excessive inflammation. The main subpopulations are: thymic (tTreg/nTreg), formed in the thymus and enriched in receptors for autoantigens; induced (iTreg/pTreg), differentiating in the periphery from naive CD4⁺ T cells. Phenotypic identification is based on the expression of Foxp3, CD25 and low levels of CD127. Suppression mechanisms include: secretion of inhibitory cytokines (IL 10, TGF β, IL 35); action of checkpoint molecules (CTLA 4, PD 1, LAG 3, TIGIT); metabolic modulation via CD39/CD73 (adenosine generation); suppression of Ca²⁺ signaling in effector lymphocytes, etc. Treg stability is maintained by epigenetic mechanisms and metabolic programs; plasticity is manifested in the formation of hybrid Treg/Th subpopulations with partial suppressor activity and the production of corresponding helper cytokines: Th1-Treg, Th2-Treg, Th17-Treg, Tfr-Treg, depending on the tissue microenvironment. Migration and tissue residency are regulated by chemokine receptors and adhesion molecules. CD69 blocks S1PR1, ensuring Treg retention in tissue. ST2 serves as a marker and functional receptor for Treg in barrier tissues and is activated by "alarm signals" (IL 33). In different organs, Tregs acquire unique transcriptomes and functional characteristics (for example, in the intestine—α4β7⁺CD103⁺; in adipose tissue—dependence on PPARγ, ID2, and BATF). They participate in maintaining tolerance, controlling inflammation, and inducing reparative processes by suppressing inflammation and switching macrophages to the M2 phenotype. Tregs provide protective control of the immune response, but in some cases (tumors, fibrosis) they can contribute to disease progression. Studying the stability, plasticity, and migration of Tregs opens up prospects for targeted immunotherapy.

тканеспецифические Т-регуляторные клеткиTh1-TregTh2-TregTh17-TregTfr-Treg-клеткитканевое микроокружениепластичность

Key words: tissue-specific T-regulatory cellsTh1-TregTh2-TregTh17-TregTfr-Treg cellstissue microenvironmentplasticity

При подготовке обзора финансовая поддержка не оказывалась

References1

Список литературы / References

Гариб Ф. Ю., Ризопулу А. П. «Роль Т регуляторных клеток в контроле и индукции воспаления» // Цитокины и воспаление. 2025. Т. 22, № 1. С. 5–11. DOI: 10.17816/CI687608.

Арсентьева Н. А., Семёнов А. В., Жебрун А. Б., Васильева Е. В., Тотолян А. А. Роль хемокинового рецептора CXCR3 и его лигандов при некоторых заболеваниях // Медицинская иммунология. 2019. Т. 21, № 4. С. 617–632. DOI: 10.15789/1563-0625-2019-4-617-632. [Arsentieva N.A., Semenov A.V., Zhebrun D.A., Vasilyeva E.V., Totolyan A.A. Role of CXCR3 chemokine receptor and its ligands in certain diseases, Medical Immunology (Russia)/ Meditsinskaya Immunologiya, 2019, Vol. 21, no. 4, pp. 617-632. doi: 10.15789/1563-0625-2019-4-617-632.]

Гариб Ф. Ю., Ризопулу А. П. «Роль Т регуляторных клеток в контроле и индукции воспаления» // Цитокины и воспаление. 2025. Т. 22, № 1. С. 5–11. DOI: 10.17816/CI687608. [Garib F.Y., Rizopulu A.P. The role of regulatory T cells in suppression and induction of inflammftion, Cytokines and inflammation. 2025;22(1):5-11. DOI: 10.17816/CI687608.]

Козлов В.А. Селекция клеток в тимусе и гомеостатическая пролиферация клеток на периферии при инфекционных процессах // Инфекция и иммунитет. 2019. Т. 9, № 5–6. С. 629–638. doi: 10.15789/2220-7619-2019-5-6-629-638. [Kozlov V.A. T cell thymic selection and peripheral homeostatic proliferation in infectious diseases // Russian Journal of Infection and Immunity = Infektsiya i immunitet, 2019, vol. 9, no. 5–6, pp. 629–638. doi: 10.15789/2220-7619-2019-5-6-629-638.]

Топтыгина А.П. Тканерезидентные клетки иммунитета в гомеостазе и репарации тканей // Медицинская иммунология, 2025. Т. 27, № 3. С. 475-484. doi: 10.15789/1563-0625-TRI-3156. [Toptygina A.P. Tissue-resident immune cells in homeostasis and tissue repair”, Medical Immunology (Russia)/ Meditsinskaya Immunologiya, 2025, Vol. 27, no. 3, pp. 475-484. doi: 10.15789/1563-0625-TRI-3156.]

Al Nabhani Z., Dulauroy S., Marques R., Cousu C., Al Bounny S., Déjardin F., Sparwasser T., Bérard M., Cerf Bensussan N., Eberl G. A weaning reaction to microbiota is required for resistance to immunopathologies in the adult. Immunity, 2019, vol. 50, no. 5, pp. 1276.e5–1288.e5. DOI: 10.1016/j.immuni.2019.02.014

Alvarez F., Istomine R., Shourian M., Pavey N., Al Aubodah T. A., Qureshi S., Gauthier L., Krawczyk P. A., Ongruk E., Elia A. J., Kronenberg M., Mak T. W. The alarmins IL 1 and IL 33 differentially regulate the functional specialisation of Foxp3(+) regulatory T cells during mucosal inflammation. Mucosal Immunology, 2019, vol. 12, no. 3, pp. 746–760. DOI: 10.1038/s41385 019 0153 5.

Alvarez F., Liu Z., Bay A., Piccirillo C. A. Deciphering the developmental trajectory of tissue resident Foxp3+ regulatory T cells. Frontiers in Immunology, 2024, vol. 15, p. 1331846. DOI: 10.3389/fimmu.2024.1331846.

Arnold P. R., Wen M., Zhang L., Ying Y., Xiao X., Chu X., et al. Suppression of Foxp3 expression by the AP 1 family transcription factor BATF3 requires partnering with Irf4. Frontiers in Immunology, 2022, vol. 13, p. 966364. DOI: 10.3389/fimmu.2022.966364.

Arpaia N., Dushek O., Lau L., Bushell A., Sasikumar P., Perez J. M., Huang W., Newell E. W., Grotenbreg G., van der Veen A. G., Goyette J., Zilbauer M., Manley N. R., Cerundolo V., van den Elzen P. A distinct function of regulatory T cells in tissue protection versus antigen tolerance. Cell, 2013, vol. 155, no. 5, pp. 1127–1140. DOI: 10.1016/j.cell.2013.08.021

Astarita J. L., Dominguez C. X., Tan C., Guillen J., Pauli M. L., Labastida R., Cebrian I., Krummel M. F. Treg specialization and functions beyond immune suppression. Clinical & Experimental Immunology, 2023, vol. 211, pp. 176–183. DOI: 10.1093/cei/uxac123.

Attias M., Al Aubodah T., Piccirillo C. A. Mechanisms of human Foxp3(+) T(reg) cell development and function in health and disease. Clinical & Experimental Immunology, 2019, vol. 197, pp. 36–51. DOI: 10.1111/cei.13290.

Bhattacharyya N. D., Feng C. G. Regulation of T helper cell fate by TCR signal strength. Frontiers in Immunology, 2020, vol. 11. DOI: 10.3389/fimmu.2020.00624.

Borthwick L. A., Wynn T. A., Haslett C., Rossi A. G., Savai R., Kolb M., Jenkins R. G., McGarry T., Groot K. R., Lloyd C. M., Sverzellati N., Papi A., Budinger G. R. S., Budinger S. C. E., Ito S., Tuder R. M., Selman M., Thannickal V. J., Kaminski N., Eickelberg O., Maher T. M. IL 33 promotes ST2 dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells. J. Immunol., 2013, vol. 190, no. 5, pp. 2457–2465. DOI: 10.4049/jimmunol.1202757

Brestoff J. R., Kim B. S., Saenz S. A., Stine R. R., Monticelli L. A., Sonnenberg G. F., Thome J. J., Farber D. L., Lutfy K., Seale P., Artis D. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature, 2015, vol. 519, no. 7542, pp. 242–246. DOI: 10.1038/nature14115

Burzyn D., Kuswanto W., Kolodin D., Shadrach J. L., Cerletti M., Jang Y., Wagers A. J., Mathis D., Benoist C. Tissue resident regulatory T cells: from phenotypic and functional specialization to therapy. Nature Reviews Immunology, 2018, vol. 18, no. 1, pp. 17–32. DOI: 10.1038/nri.2017.125

Campbell C., McKenney P. T., Konstantinovsky D., Isaeva O. I., Schizas M., Verter J., Mai C., Jin W. B., Guo C. J., Violante S., Bettini M., Vicencio J. M., Cheroutre H., Pamer E. G. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature, 2020, vol. 581, no. 7809, pp. 475–479. DOI: 10.1038/s41586 020 2193 0.

Chen S. Q., Wang X., Li J., Zhang Y., Liu H., Yang L., Wang Y., Zhang X., Liu Y., Zhao L., Sun X., Wang L. Epigenetically modifying the locus for generation of stable antigen specific Tregs as cellular therapeutics. American Journal of Transplantation, 2020, vol. 20, no. 9, pp. 2366–2379. DOI: 10.1111/ajt.15987.

Chen W., Huang W., Xue Y., Chen Y., Qian W., Ma J., August A., Wang J., Zheng S. G., Lin J. Neuropilin 1 identifies a new subpopulation of TGF beta induced Foxp3(+) regulatory T cells with potent suppressive function and enhanced stability during inflammation. Frontiers in Immunology, 2022, vol. 13, p. 900139. DOI: 10.3389/fimmu.2022.900139.

Cipolletta D., Feuerer M., Li A., Kamei N., Lee J., Shoelson S.E., Benoist C., Mathis D. PPAR γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 2012, vol. 486, no. 7404, pp. 549–553. DOI: 10.1038/nature11132

Cruz Morales E., Hart A. P., Fossett G. M., Laufer T. M. Helios(+) and RORγt(+) Treg populations are differentially regulated by MHCII, CD28, and ICOS to shape the intestinal Treg pool. Mucosal Immunology, 2023, vol. 16, pp. 264–274. DOI: 10.1016/j.mucimm.2023.02.007.

Cvetkovski F., Östman S., Yuan F., Klarqvist R.R.H., Karlsson M.C. Cutaneous regulatory T cells in health and disease. Front. Immunol., 2016, vol. 7, pp. 293. DOI: 10.3389/fimmu.2016.00293

Dikiy S., Rudensky A. Y. Principles of regulatory T cell function. Immunity, 2023, vol. 56, pp. 240–255. DOI: 10.1016/j.immuni.2023.01.001.

Ding Z., Cai T., Tang J., Sun H., Qi X., Zhang Y., Wang J., Liu Y., Chen X., Li W., Liu L., Gao X., Wang P. Setd2 supports Gata3(+)ST2(+) thymic derived Treg cells and suppresses intestinal inflammation. Nature Communications, 2022, vol. 13, p. 7468. DOI: 10.1038/s41467 022 35250 0.

Edwards J.P., Thornton A.M., Shevach E.M. Release of active TGF β1 from the latent TGF β1/GARP complex on T regulatory cells is mediated by integrin β8. J. Immunol., 2014, vol. 193, no. 6, pp. 2843–2849. DOI: 10.4049/jimmunol.1401102

Faustino L. D., Griffith J. W., Rahimi R. A., Nepal K., Hamilos D. L., Cho J. L., Rosas I. O., Herbst R., Rosenthal P., Luster A. D. Interleukin 33 activates regulatory T cells to suppress innate gamma delta T cell responses in the lung. Nature Immunology, 2020, vol. 21, pp. 1371–1383. DOI: 10.1038/s41590 020 0785 3.

Gao N., Yang L., Wang Y., Li X., Zhang Y., Liu J., Zhao H., Chen X., Sun L. Contribution of Th2-like Treg cells to the pathogenesis of Takayasu’s arteritis. Clin. Exp. Rheumatol., 2020, vol. 38, Suppl. 124, pp. 48–54. DOI: 10.1007/s10067-020-05187-x

Georgiev P, Benamar M, Han S, Haigis MC, Sharpe AH, Chatila TA. Regulatory T cells in dominant immunologic tolerance. J Allergy Clin Immunol. (2024) 153:28–41. doi: 10.1016/j.jaci.2023.09.025

Gocher Demske A.M., Cui J., Szymczak Workman A.L., Vignali K.M., Latini J.N., Pieklo G.P., Kimball J.C., Avery L., Cipolla E.M., Huckestein B.R., Hedden L., Meisel J., Alcorn J.F., Kane L.P., Workman C.J., Vignali D.A.A. IFNγ induction of TH1 like regulatory T cells controls antiviral responses. Nat. Immunol., 2023, vol. 24, no. 5, pp. 841–854. DOI: 10.1038/s41590 023 01453 w

Griffith J.W., Sokol C.L., Luster A.D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol., 2014, vol. 32, pp. 659–702. DOI: 10.1146/annurev immunol 032713 120145

Halim L., Romano M., McGregor R., Correa I., Pavlidis P., Grageda N., Hoong S. J., Yuksel M., Jassem W., Hannen R. F., Ong M., McKinney O., Hayee B. H., Karagiannis S. N., Powell N., Lechler R. I., Nova Lamperti E., Lombardi G. An atlas of human regulatory T helper like cells reveals features of Th2 like Tregs that support a tumorigenic environment. Cell Rep., 2017, vol. 20, no. 3, pp. 757–770. DOI: 10.1016/j.celrep.2017.06.079

Herppich S., Toker A., Pietzsch B., Kitagawa Y., Ohkura N., Miyao T., Floess S., Hori S., Sakaguchi S., Huehn J. Dynamic imprinting of the Treg cell specific epigenetic signature in developing thymic regulatory T cells. Frontiers in Immunology, 2019, vol. 10, p. 2382. DOI: 10.3389/fimmu.2019.02382.

Joudi A. M., Reyes Flores C. P., Singer B. D. Epigenetic control of regulatory T cell stability and function: implications for translation. Frontiers in Immunology, 2022, vol. 13, p. 861607. DOI: 10.3389/fimmu.2022.861607.

Kaiser J., Schmidt Supprian M., Liston A., Darrigues J., Adoue V., Gros M., Binet B., Perals C., Thiault N., Fazilleau N., Joffre O. P., Robey E. A., van Meerwijk J. P. M., Romagnoli P. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nature Immunology, 2023, vol. 24, no. 5, pp. 789–798. DOI: 10.1038/s41594 023 01015 x.

Kang J.H., Zappasodi R. Modulating Treg stability to improve cancer immunotherapy. Trends Cancer, 2023, vol. 9, no. 11, pp. 911–927. DOI: 10.1016/j.trecan.2023.07.015.

Kempkes R. W. M., Joosten I., Koenen H., He X. Metabolic pathways involved in regulatory T cell functionality. Frontiers in Immunology, 2019, vol. 10, p. 2839. DOI: 10.3389/fimmu.2019.02839.

Khan A.K., Bradley D., Shantaram D., Smith A., Hsueh W.A. Adipose tissue regulatory T cells: mechanisms of induction and function. Front. Immunol., 2021, vol. 12, pp. 643789. DOI: 10.3389/fimmu.2021.643789

Khantakova J. N., Bulygin A. S., Sennikov S. V. The regulatory T cell memory phenotype: what we know. Cells, 2022, vol. 11, no. 10, p. 1687. DOI: 10.3390/cells11101687.

Khatun A., Wu X., Qi F., Gai K., Kharel A., Kudek M. R., Wang Y., Zheng S. G., Wan Y. BATF is required for Treg homeostasis and stability to prevent autoimmune pathology. Advanced Science, 2023, vol. 10, no. 28, p. e2206692. DOI: 10.1002/advs.202206692.

Kim K.S., Hong S.W., Han D., Yi J., Jung J., Yang B.G., Lee J.Y., Lee M., Surh C.D. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science, 2016, vol. 351, no. 6275, pp. 858–863. DOI: 10.1126/science.aac5560.

Knoedler S., Knoedler L., Kauke-Navarro M., Rinkevich Y., Hundeshagen G., Harhaus L., Kneser U., Pomahac B., Orgill D.P., Panayi A.C. Regulatory T cells in skin regeneration and wound healing. Mil Med Res, 2023, vol. 10, no. 1, p. 49. DOI: 10.1186/s40779-023-00484-6. PMID: 37867188; PMCID: PMC10591349.

Lam A. J., Uday P., Gillies J. K., Levings M. K. Helios is a marker, not a driver, of human Treg stability. European Journal of Immunology, 2022, vol. 52, pp. 75–84. DOI: 10.1002/eji.202149318.

Li X., Chaudhry A., Reyes A., Huang Y., Tieu R.K., deRoos P., Jin W., Raab M., Pan F., Su S., Zheng Y. Function of a Foxp3 cis element in protecting regulatory T cell identity. Cell, 2014, vol. 158, no. 4, pp. 734–748. DOI: 10.1016/j.cell.2014.06.049

Linterman M.A., Beura L.D., Yu D., Burton A.R., Newton R., Rankin A.L., Smith K.G.C., Mackay C.R., Artis D., Vinuesa C.G. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med., 2011, vol. 17, no. 8, pp. 975–982. DOI: 10.1038/nm.2426

Liston A., Piccirillo C. A. Developmental plasticity of murine and human Foxp3(+) regulatory T cells. Advances in Immunology, 2013, vol. 119, pp. 85–106. DOI: 10.1016/B978 0 12 407707 2.00003 5.

Liu Y., Wang L., Li D., Zhang Y., Chen X., Zheng Y., Sun J., Liu Y., Sun Y., Wang Y., Li Y., Zhang Y.IL 33 induces the expansion of skin resident regulatory T cells. J. Immunol., 2014, vol. 192, no. 11, pp. 5174–5181. DOI: 10.4049/jimmunol.1302976

Lui P.P., Xu J.Z., Aziz H., Wong C.K.C., Li G., Chan K.M., Cheung P.P.H., Tang B.M.C., Chu A.C.Y., Man C.Y.Y., Ngai S.M.Y., Ho S.S.W., Chan C.L.K., Leung K.C.W., Li K.Y.C., Wong W.K.Y., Lau C.S.C., Lee J.H.Y., Chan T.H.M., Chung J.P.W. Jagged 1+ skin Tregs modulate cutaneous wound healing. Sci. Rep., 2024, vol. 14, p. 20999. DOI: 10.1038/s41598 024 71512 1

Mackay L. K., Minnich M., Kragten N. A., Liao Y., Nota B., Seillet C., Zaid A., Man K., Preston S., Freestone D., Braun A., Wynne Jones E., Behr F. M., Stark R., Pellicci D. G., Godfrey D. I., Belz G. T., Pellegrini M., Gebhardt T., Busslinger M., Shi W., Carbone F. R., van Lier R. A. W., Kallies A., van Gisbergen K. P. J. M. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science, 2016, vol. 352, no. 6284, pp. 459–463. DOI: 10.1126/science.aad2035.

Mempel T.R., Marangoni F. Guidance factors orchestrating regulatory T cell positioning in tissues during development, homeostasis, and response. Immunol. Rev., 2019, vol. 289, pp. 129–141. DOI: 10.1111/imr.12761

Miragaia R. J., Gomes T., Chomka A., Jardine L., Riedel A., Hegazy A. N., Whibley N., Tucci A., Chen X., Lindeman I., Emerton G., Krausgruber T., Haniffa M., Powrie F., Teichmann S. A. Single cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity, 2019, vol. 50, no. 2, pp. 493–504.e7. DOI: 10.1016/j.immuni.2019.01.001.

Muñoz Rojas A. R., Mathis D. Tissue regulatory T cells: regulatory chameleons. Nature Reviews Immunology, 2021, vol. 21, pp. 597–611. DOI: 10.1038/s41577 021 00519 w.

Ohnmacht C., Park J.-H., Cording S., Wing J.B., Atarashi K., Obata Y., Gaboriau Routhiau V., Marques R., Dulauroy S., Fedoseeva M., Stanckzuk A.J., Sawa S., Lochner M., Rodriguez-Pinto D., Brandl K., Eberl G., Hugot J.-P., Boneca I.G., Ueda Y., Honda K., Taniguchi M., Sparwasser T., Vivier E., Diefenbach A., Benoist C., Mathis D. The microbiota regulates type 2 immunity through RORγt+ T cells. Science, 2015, vol. 349, no. 6251, pp. 989–993. DOI: 10.1126/science.aac4263

Ono M. Control of regulatory T cell differentiation and function by T cell receptor signalling and Foxp3 transcription factor complexes. Immunology, 2020, vol. 160, no. 1, pp. 24–37. DOI: 10.1111/imm.13178.

Panduro M., Melumad A., Kadouri N., Pollard K.S., Rudensky A.Y. Tissue specific signals control reversible programming of natural regulatory T cells. Cell, 2016, vol. 165, no. 7, pp. 1787–1801. DOI: 10.1016/j.cell.2016.04.054

Park J. E., Botting R. A., Domínguez Conde C., Popescu D. M., Lavaert M., Kunz D. J., Goh I., Lee J., Simoni Y., Fletcher J. M., Goh W. S. S., Newell E. W., Haniffa M. A cell atlas of human thymic development defines T cell repertoire formation. Science, 2020, vol. 367, no. 6484, p. eaay3224. DOI: 10.1126/science.aay3224.

Pastille E., Wasmer M. H., Adamczyk A., Vu V. P., Mager L. F., Phuong N. N. T., Kruglov A. A., Nunes Alves C., Heikenwälder M., Kühl A. A., Neurath M. F., Scheffold A. The IL 33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer. Mucosal Immunology, 2019, vol. 12, pp. 990–1003. DOI: 10.1038/s41385 019 0176 y.

Patterson S.J., Pesenacker A. M., Wang A. Y., Gillies J., Mojibian M., Morishita K., Tan R., Kieffer T. J., Verchere C. B., Panagiotopoulos C., Levings M. K. T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression. J. Clin. Invest., 2016, vol. 126, no. 3, pp. 1039–1051. DOI: 10.1172/JCI83987

Peter S. E., Riaz F., Li Y., Zhao X., Pan F. Immunomodulatory roles of regulatory T cells in cutaneous wound healing: mechanisms and therapeutic opportunities. Front. Immunol., 2026, vol. 17, p. 1737438. DOI: 10.3389/fimmu.2026.1737438. PMID: 41924280; PMCID: PMC13037489

Rankin L. C., Kaiser K. A., de Los Santos Alexis K., Park H., Uhlemann A. C., Gray D. H. D., Diefenbach A., Rudensky A. Y. Dietary tryptophan deficiency promotes gut RORγt(+) Treg cells at the expense of Gata3(+) Treg cells and alters commensal microbiota metabolism. Cell Reports, 2023, vol. 42, p. 112135. DOI: 10.1016/j.celrep.2023.112135.

Rapp M., Wintergerst M. W. M., Kunz W. G., Vetter V. K., Knott M. M. L., Lisowski D., Haubner S., Moder S., Thaler R., Eiber S., Meyer B., Röhrle N., Piseddu I., Grassmann S., Layritz P., Kühnemuth B., Stutte S., Bourquin C., von Andrian U. H., Endres S., Anz D. CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes. J. Exp. Med., 2019, vol. 216, no. 5, pp. 1170–1181. DOI: 10.1084/jem.20170277

Reichert L.C., Zielinski C.E., Kretschmer K., Floess S., Sparwasser T., Huehn J., Schmitt V.H., Baumann L., Schmitt M.A., Schmitt D., Kramer B., Geffers R., Heydrich C., Drees C., Buer J., Hamann A., Huehn S. Amphiregulin from regulatory T cells promotes tissue repair. Sci. Immunol., 2020, vol. 5, no. 48, p. aba7479. DOI: 10.1126/sciimmunol.aba7479. механизмы участия Treg в реэпителиализации и регенерации кожи.

Romagnani C., Annunziato F. Human regulatory T cells and their role in autoimmune disease. Adv. Immunol., 2017, vol. 136, pp. 1–49. DOI: 10.1016/bs.ai.2017.07.001

Rosenblum M. D., Grinstein S. M., Grinberg A., Ansel K. M., Kupper T. S. Phenotype and function of tissue resident memory T cells. Nature Reviews Immunology, 2019, vol. 19, no. 8, pp. 465–478. DOI: 10.1038/s41577 019 0179 4.

Russler Germain E. V., Rengarajan S., Hsieh C. S. Antigen specific regulatory T cell responses to intestinal microbiota. Mucosal Immunology, 2017, vol. 10, no. 6, pp. 1375–1386. DOI: 10.1038/mi.2017.65.

Saigusa R., Otsuka T., Kawakami T., Kanda H., Tanaka S., Asano Y., Ihn H. Fli1 haploinsufficient dermal fibroblasts promote skin localized transdifferentiation of Th2 like regulatory T cells. Arthritis Res. Ther., 2018, vol. 20, p. 23. DOI: 10.1186/s13075 017 1498 x

Saigusa R., Winkels H., Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol., 2020, vol. 17, pp. 387–401. DOI: 10.1038/s41569-020-0352-5.

Sakaguchi S., Mikami N., Wing J. B., Tanaka A., Ichiyama K., Ohkura N. Regulatory T cells and human disease. Annual Review of Immunology, 2020, vol. 38, pp. 541–566. DOI: 10.1146/annurev-immunol-042718-041717.

Sakaguchi S., Vignali D. A., Rudensky A. Y., Niec R. E., Waldmann H. The plasticity and stability of regulatory T cells. Nature Reviews Immunology, 2013, vol. 13, no. 6, pp. 461–467. DOI: 10.1038/nri3464.

Satitsuksanoa P., Jansen K., Globinska A., van de Veen W., Akdis M. Regulatory immune mechanisms in tolerance to food allergy. Frontiers in Immunology, 2018, vol. 9, p. 2939. DOI: 10.3389/fimmu.2018.02939.

Schwarz A., Schumacher M., Pfaff D., Schumacher K., Jarius S., Balint B., Hartmann M., Paul F., Aktas O., Probst C., Zipp F., Flachenecker P. Fine tuning of regulatory T cell function: the role of calcium signals and naive regulatory T cells for regulatory T cell deficiency in multiple sclerosis. J. Immunol., 2013, vol. 190, no. 10, pp. 4965–4970. DOI: 10.4049/jimmunol.1203224

Shevyrev D., Tereshchenko V. Treg heterogeneity, function, and homeostasis. Front. Immunol., 2020, vol. 10, p. 3100. DOI: 10.3389/fimmu.2019.03100

Shi H., Chi H. Metabolic control of Treg cell stability, plasticity, and tissue specific heterogeneity. Front. Immunol., 2019, vol. 10, p. 2716. DOI: 10.3389/fimmu.2019.02716.

Sivasami P., Elkins C., Diaz Saldana P. P., Goss K., Peng A., Hamersky M. T., Wang Y., Li X., Chen Z., Liu Y., Zheng Y. Obesity induced dysregulation of skin resident PPARγ(+) Treg cells promotes IL 17A mediated psoriatic inflammation. Immunity, 2023, vol. 56, no. 8, pp. 1844–1861.e6. DOI: 10.1016/j.immuni.2023.06.021.

Spath S., Roan F., Presnell S. R., Hollbacher B., Ziegler S. F. Profiling of Tregs across tissues reveals plasticity in ST2 expression and hierarchies in tissue specific phenotypes. iScience, 2022, vol. 25, p. 104998. DOI: 10.1016/j.isci.2022.104998.

Sun L., Su Y., Jiao A., Wang X., Zhang B. T cells in health and disease. Signal Transduct Target Ther., 2023, vol. 8, no. 1, p. 187. DOI: 10.1038/s41392 023 01471 y

Tai X., Indart A., Rojano M., Guo J., Apenes N., Kadakia T., Craveiro M., Alag A., Etzensperger R., Badr M. E., Zhang F., Zhang Z., Mu J., Guinter T., Crossman A., Granger L., Sharrow S., Zhou X., Singer A. How autoreactive thymocytes differentiate into regulatory versus effector CD4+ T cells after avoiding clonal deletion. Nature Immunology, 2023, vol. 24, pp. 637–651. DOI: 10.1038/s41590 023 01469 2.

Thornton A. M., Lu J., Korty P. E., Kim Y. C., Martens C., Sun P. D., Bhandula V., Lacy K. E., Shevach E. M. Helios(+) and Helios(−) Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires. European Journal of Immunology, 2019, vol. 49, no. 3, pp. 398–412. DOI: 10.1002/eji.201847935.

Trujillo Ochoa J. L., Kazemian M., Afzali B. The role of transcription factors in shaping regulatory T cell identity. Nat. Rev. Immunol., 2023, vol. 23, pp. 842–856. DOI: 10.1038/s41577 023 00869 9

van der Veeken J., Campbell C., Pritykin Y., Schizas M., Verter J., Hu W., Wang Z. M., Matheis F., Mucida D., Charbonnier L. M., Rudensky A. Y. Genetic tracing reveals transcription factor Foxp3 dependent and Foxp3 independent functionality of peripherally induced Treg cells. Immunity, 2022, vol. 55, no. 7, pp. 1173.e7–1184.e7. DOI: 10.1016/j.immuni.2022.05.010.

van der Veeken J., Glasner A., Zhong Y., Hu W., Wang Z. M., Bou Puerto R., Kretschmer K., Zheng Y. The transcription factor Foxp3 shapes regulatory T cell identity by tuning the activity of trans acting intermediaries. Immunity, 2020, vol. 53, no. 5, pp. 971–984.e5. DOI: 10.1016/j.immuni.2020.10.010.

Von Knethen, A., Heinicke, U., Weigert, A., Zacharowski, K., & Brüne, B. Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells // International Journal of Molecular Sciences. 2020. Vol. 21, № 7. Art. 2356. DOI: 10.3390/ijms21072356.

Wang J., Zhao X., Wan Y. Y. Intricacies of TGF β signaling in Treg and Th17 cell biology. Cellular & Molecular Immunology, 2023, vol. 20, pp. 1002–1022. DOI: 10.1038/s41423 023 01036 7.

Wang L., Liang Y., Zhao C., Ma P., Zeng S., Ju D., Zhao M., Yu M., Shi Y. Regulatory T cells in homeostasis and disease: molecular mechanisms and therapeutic potential. Signal Transduct Target Ther, 2025, vol. 10, p. 345. DOI: 10.1038/s41392 025 02326 4

Wang Y., Li J., Nakahata S., Iha H. Complex role of regulatory T cells (Tregs) in the tumor microenvironment: their molecular mechanisms and bidirectional effects on cancer progression. Int. J. Mol. Sci., 2024, vol. 25, no. 13, p. 7346. DOI: 10.3390/ijms25137346

Watson M. J., Vignali P. D. A., Mullett S. J., Overacre Delgoffe A. E., Peralta R. M., Grebinoski S., Menk A. V., Rittenhouse N. L., Depeaux K., Whetstone R. D., Vignali D. A. A., Hand T. W., Poholek A. C., Morrison B. M., Rothstein J. D., Wendell S. G., Delgoffe G. M. Metabolic support of tumour infiltrating regulatory T cells by lactic acid. Nature, 2021, vol. 591, pp. 645–651. DOI: 10.1038/s41586 020 03045 2

Worthington J. J., Kelly A., Smedley C., Bauché D., Campbell S., Marie J. C., Travis M. A. Integrin αvβ8 mediated TGF β activation by effector regulatory T cells is essential for suppression of T cell mediated inflammation. Immunity, 2015, vol. 42, no. 5, pp. 903–915. DOI: 10.1016/j.immuni.2015.04.012

Worthington J.J., Evans C., Veldhoen M. Tissue-resident regulatory T cells: local specialists. Immunol. Rev., 2015, vol. 263, no. 1, pp. 51–65. DOI: 10.1111/imr.12232

Xing S, Gai K, Li X, Shao P, Zeng Z, Zhao X, Chen X., Paradee W. J., Xue H. H. Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells. J Exp Med., 2019, Vol. 216, No. 4, pp. 847–66. doi: 10.1084/jem.20182010

Zhang H. L., Zheng Y. J., Pan Y. D., Xie C., Sun H., Zhang Y. H., Yuan M. Y., Song B. L., Chen J. F. Regulatory T cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity. Mucosal Immunol., 2016, vol. 9, no. 2, pp. 391–400. DOI: 10.1038/mi.2015.68

Zhang P., Wang J., Miao J., Zhu P. The dual role of tissue regulatory T cells in tissue repair: return to homeostasis or fibrosis. Front. Immunol., 2025, vol. 16, p. 1560578. DOI: 10.3389/fimmu.2025.1560578.

The authors declare that there are no conflicts of interest present.