Regulation of the T cell response

Abstract

Summary: The T cell branch of the immune system can respond to a virtually infinite variety of exogenous antigens, thus including the possibility of self‐antigen recognition and dangerous autoimmune reactions. Therefore, regulatory mechanisms operate both during ontogeny within the thymus and after birth in the periphery. The control of self‐reactive T cells occurs through a process of negative selection that results in apoptosis of T cells showing high affinity for self‐peptides expressed at the thymic level by means of promiscuous gene expression. Self‐reactive T cells escaped to negative selection are controlled in the periphery by other regulatory mechanisms, the most important being natural Foxp3+ T regulatory (Treg) cells. Regulation is also required to control excessive effector T cell responses against exogenous antigens, when they become dangerous for the body. Three types of effector T cells have been recognized: T helper 1 (Th1) cells, which are protective against intracellular bacteria; Th2 cells, which play some role in the protection against nematodes, but are responsible for allergic reactions; Th17 cells, which are probably effective in the protection against extracellular bacteria, but also play a role in the amplification of autoimmune disorders. Abnormal or excessive Th effector responses are regulated by different mechanisms. Redirection or immune deviation of Th1‐ or Th2‐dominated responses is provided by cytokines [interferon‐γ (IFN‐γ) vs. interleukin‐4 (IL‐4)] produced by the same cell types and by the CXCR3‐binding chemokines CXCL4 and CXCL10. Moreover, both Th1 and Th2 responses can be suppressed by adaptive Treg cells through contact‐dependent mechanisms and/or the production of IL‐10 and transforming growth factor‐β (TGF‐β). Finally, TGF‐β1 can promote the development of both Th17 effector and adaptive Treg cells, while the contemporaneous production of IL‐6 contributes to the development of Th17 cells, but inhibits Treg cells. The development of Th17 cells is also down‐regulated by IL‐4 produced by Th2 cells and by IFN‐γ produced by Th1 cells.