T Cell Receptor Signaling and Immune Tolerance: From Autoimmunity to Cancer Immunity.

The intensity of T cell receptor (TCR) signaling controls thymic positive and negative selection of conventional T cells (Tconv cells) and regulatory T cells (Treg cells), as well as their peripheral activation. Accordingly, the effects of graded TCR signal reduction manifest as a disease spectrum encompassing T cell immune deficiency, latent autoimmunity, and overt autoimmune disease. TCR signal attenuation to a certain range-for example, through hypomorphic mutation of the ZAP-70 (ζ chain-associated protein-70) molecule or reduced expression of its normal form-shifts the TCR repertoire of Tconv and Treg cells toward higher self-reactivity and hampers Treg cell generation. These alterations together lead to spontaneous development of various T cell-mediated autoimmune and inflammatory diseases. Additional host genetic and environmental factors exert secondary effects on disease phenotype and manifestation. In addition, pharmacological attenuation of TCR signaling to a certain range in peripheral T cells can selectively reduce mature Treg cells and evoke effective antitumor immune responses. Collectively, TCR-proximal signaling is a key target for controlling autoimmunity and cancer immunity.