The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells.
Numerous studies over the past 10 years have demonstrated the importance of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells (nTregs) in immune regulation. We analyzed the mechanism of action of nTregs in a well-characterized model of autoimmune gastritis and demonstrated that nTregs act at an early stage of disease progression to inhibit the differentiation of naïve T cells to pathogenic T-helper 1 effectors. The effects of nTregs in this model are not antigen-specific but are mediated by activation of the nTregs by ubiquitous self-peptide major histocompatibility complex class II complexes together with cytokines released by activated effector cells. Studies in vitro confirmed that some nTregs exist in an activated state in vivo and can be activated to exert non-specific suppressor effector function by stimulation with interleukin-2 in the absence of engagement of their T-cell receptor. Natural Tregs can differentiate in vitro to exhibit potent granzyme B-dependent, partially perforin-independent cytotoxic cells that are capable of specifically killing antigen-presenting B cells. Natural Treg-mediated killing of antigen-presenting cells may represent one pathway by which they can induce long-lasting suppression of autoimmune disease.
Shevach
Ethan M
EM
Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. eshevach@niaid.nih.gov
DiPaolo
Richard A
RA
Andersson
John
J
Zhao
Dong-Mei
DM
Stephens
Geoffrey L
GL
Thornton
Angela M
AM
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D015704:CD4 Antigens / Q000032:analysis; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000032:analysis; D005756:Gastritis / Q000276:immunology*; D006801:Humans; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D015375:Receptors, Interleukin-2