Control of T-cell activation by CD4+ CD25+ suppressor T cells.
Depletion of the minor ( approximately 10%) subpopulation of CD4+ T cells that co-expresses CD25 (interleukin (IL)-2 receptor alpha-chain) by thymectomy of neonates on the third day of life or by treatment of adult CD4+ T cells with anti-CD25 and complement results in the development of organ-specific autoimmunity. Autoimmune disease can be prevented by reconstitution of the animals with CD4+ CD25+ cells. CD4+ CD25+-mediated protection of autoimmune gastritis does not require the suppressor cytokines IL-4, IL-10, or transforming growth factor (TGF)-beta. Mice that express a transgenic T-cell receptor (TCR) derived from a thymectomized newborn that recognizes the gastric parietal cell antigen H/K ATPase all develop severe autoimmune gastritis very early in life. CD4+ CD25+ T cells are also powerful suppressors of the activation of both CD4+ and CD8+ T cells in vitro. Suppression is mediated by a cell contact-dependent, cytokine-independent T-T interaction. Activation of CD4+ CD25+ via their TCR generates suppressor effector cells that are capable of non-specifically suppressing the activation of any CD4+ or CD8+ T cell. Activation of suppressor effector function is independent of co-stimulation mediated by CD28/CTLA-4 interactions with CD80/CD86. We propose that CD4+ CD25+ T cells recognize organ-specific antigens, are recruited to sites of autoimmune damage where they are activated by their target antigen, and then physically interact with autoreactive CD4+ or CD8+ effector cells to suppress the development of autoimmune disease.
Shevach
E M
EM
Cellular Immunology Section, Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ems1@mail.nih.gov
McHugh
R S
RS
Piccirillo
C A
CA
Thornton
A M
AM
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division; D006801:Humans; D008213:Lymphocyte Activation; D009928:Organ Specificity; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D019076:Transgenes
D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2