Dynamics of peripheral tolerance and immune regulation mediated by Treg.
Peripheral self-tolerance and immune homeostasis are maintained, at least in part, by the balance between Treg and effector T cells. Naturally, arising CD25(+)CD4(+) Treg, which express the transcription factor Foxp3, suppress the activation and proliferation of other lymphocytes in multiple ways. A CTLA-4-dependent suppressive mechanism is shared by every Foxp3(+) Treg at any location and its disruption breaches self-tolerance and immune homeostasis, suggesting that it is a core mechanism of suppression. Depending on the environment, Foxp3(+) Treg also differentiate to exhibit additional suppressive mechanisms, including the secretion of immunosuppressive cytokines. Naïve T cells acquire Foxp3 expression and suppressive activity under certain in vivo and in vitro conditions, whereas some Foxp3(+) T cells may lose Foxp3 and suppressive activity following proliferation in an IL-2-deficient environment. Moreover, activated effector T cells frequently secrete suppressive cytokines, such as IL-10, in a negative feedback fashion. These findings, when taken together, indicate that peripheral immune tolerance and homeostasis are dynamically maintained by functional differentiation within the Foxp3(+) population, occasional conversion between Treg and non-Treg cells, and the interactions among them. These dynamics provide ample opportunities for immune intervention for the benefit of the host.
Sakaguchi
Shimon
S
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. shimon@frontier.kyoto-u.ac.jp
Wing
Kajsa
K
Yamaguchi
Tomoyuki
T
D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors