Guardians of Immune Tolerance: Regulatory T Cells

MING Kang, ZHANG Huiyuan, HU Hongbo

Abstract

Shimon Sakaguchi, a Japanese scientist, together with Mary E. Brunkow and Fred Ramsdell, American scientists, were jointly awarded the 2025 Nobel Prize in Physiology or Medicine for their pioneering discoveries in the field of peripheral immune tolerance. This review summarizes the Nobel Prize-winning research on immune tolerance and discusses the development, functions, and therapeutic applications of regulatory T cell (Treg)-based interventions. These seminal studies on immune tolerance underscore a central immunological concept—a healthy immune system relies not only on its robust capacity to eliminate pathogens and mutated cells, but also on the precise inhibitory (or “brake”) and tolerance mechanisms. This concept will help deepen our understanding of key medical challenges such as autoimmune diseases, transplant rejection, and tumor immunity. It will spur the development of a series of therapeutic strategies targeting peripheral immune tolerance and Treg cells and advance research in precision immune regulation.

 

Keywords: Nobel Prize, Peripheral immune tolerance, Regulatory T cells, Review

 

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References


GERSHON R K, KONDO K. Infectious immunological tolerance. Immunology, 1971, 21(6): 903-914.

GERSHON R K, KONDO K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology, 1970, 18(5): 723-737.

SAKAGUCHI S, TAKAHASHI T, NISHIZUKA Y. Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of lyt-1 effector cells for oocytes damage after adoptive transfer. J Exp Med, 1982, 156(6): 1565-1576. doi: 10.1084/jem.156.6.1565.

SAKAGUCHI S, SAKAGUCHI N, ASANO M, et al. Immunologic self-tolerance maintained by activated t cells expressing IL-2 receptor alpha-chains (cd25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol, 1995, 155(3): 1151-1164. doi: 10.4049/jimmunol.155.3.1151.

BRUNKOW M E, JEFFERY E W, HJERRILD K A, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet, 2001, 27(1): 68-73. doi: 10.1038/83784.

WILDIN R S, RAMSDELL F, PEAKE J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet, 2001, 27(1): 18-20. doi: 10.1038/83707.

HORI S, NOMURA T, SAKAGUCHI S. Control of regulatory T cell development by the transcription factor foxp3. Science, 2003, 299(5609): 1057-1061. doi: 10.1126/science.1079490.

KHATTRI R, COX T, YASAYKO S A, et al. An essential role for scurfin in CD4+CD25+ T regulatory cells. Nat Immunol, 2003, 4(4): 337-342. doi: 10.1038/ni909.

FONTENOT J D, GAVIN M A, RUDENSKY A Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol, 2003, 4(4): 330-336. doi: 10.1038/ni904.

SHIRAFKAN F, HENSEL L, RATTAY K. Immune tolerance and the prevention of autoimmune diseases essentially depend on thymic tissue homeostasis. Front Immunol, 2024, 15: 1339714. doi: 10.3389/fimmu. 2024.1339714.

OWEN R D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science, 1945, 102(2651): 400-401. doi: 10.1126/science.102.2651.400.

ADA G. The enunciation and impact of macfarlane burnet's clonal selection theory of acquired immunity. Immunol Cell Biol, 2008, 86(2): 116-118. doi: 10.1038/sj.icb.7100156.

BILLINGHAM R E, BRENT L, MEDAWAR P B. Actively acquired tolerance of foreign cells. Nature, 1953, 172(4379): 603-606. doi: 10.1038/ 172603a0.

STEELE E J, ROTHENFLUH H S, ADA G L, et al. Affinity maturation of lymphocyte receptors and positive selection of t cells in the thymus. Immunol Rev, 1993, 135: 5-49. doi: 10.1111/j.1600-065x.1993.tb00642.x.

HOGQUIST K A, JAMESON S C, HEATH W R, et al. T cell receptor antagonist peptides induce positive selection. Cell, 1994, 76(1): 17-27. doi: 10.1016/0092-8674(94)90169-4.

TAKABA H, TAKAYANAGI H. The mechanisms of t cell selection in the thymus. Trends Immunol, 2017, 38(11): 805-816. doi: 10.1016/j.it.2017.07.010.

ANDERSON M S, VENANZI E S, KLEIN L, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science, 2002, 298(5597): 1395-1401. doi: 10.1126/science.1075958.

TAKABA H, MORISHITA Y, TOMOFUJI Y, et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell, 2015, 163(4): 975-987. doi: 10.1016/j.cell.2015.10.013.

NEMAZEE D. Mechanisms of central tolerance for b cells. Nat Rev Immunol, 2017, 17(5): 281-294. doi: 10.1038/nri.2017.19.

GOODNOW C C, CROSBIE J, ADELSTEIN S, et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature, 1988, 334(6184): 676-682. doi: 10.1038/334676a0.

GALLEGOS A M, BEVAN M J. Central tolerance: good but imperfect. Immunol Rev, 2006, 209: 290-296. doi: 10.1111/j.0105-2896.2006.00348.x. BROWN C C, RUDENSKY A Y. Spatiotemporal regulation of peripheral T cell tolerance. Science, 2023, 380(6644): 472-478. doi: 10.1126/science. adg6425.

ELTANBOULY M A, NOELLE R J. Rethinking peripheral T cell tolerance: checkpoints across a T cell's journey. Nat Rev Immunol, 2021, 21(4): 257-267. doi: 10.1038/s41577-020-00454-2.

CUROTTO De LAFAILLE M A, LAFAILLE J J. Natural and adaptive foxp3+ regulatory T cells: More of the same or a division of labor?Immunity, 2009, 30(5): 626-635. doi: 10.1016/j.immuni.2009.05.002. IRLA M. Instructive cues of thymic T cell selection. Annu Rev Immunol, 2022, 40: 95-119. doi: 10.1146/annurev-immunol-101320-022432.

LIO C W, HSIEH C S. A two-step process for thymic regulatory T cell development. Immunity, 2008, 28(1): 100-111. doi: 10.1016/j.immuni. 2007.11.021.

TAI X, ERMAN B, ALAG A, et al. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity, 2013, 38(6): 1116-1128. doi: 10.1016/j.immuni.2013.02.022.

MARSHALL D, SINCLAIR C, TUNG S, et al. Differential requirement for il-2 and IL-15 during bifurcated development of thymic regulatory T cells. J Immunol, 2014, 193(11): 5525-5533. doi: 10.4049/jimmunol.1402144.

BURCHILL M A, YANG J, VOGTENHUBER C, et al. IL-2 receptor beta-dependent stat5 activation is required for the development of foxp3+ regulatory T cells. J Immunol, 2007, 178(1): 280-290. doi: 10.4049/jimmunol.178.1.280.


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