Balancing regulatory and self-reactive T cells

Self-tolerance is maintained by the negative selection of self-reactive T cells in the thymus and the generation of regulatory T (T_Reg) cells to control self-reactive T cells in the periphery. How T cell receptor (TCR) signal strength controls these processes has not been clearly defined. In this study, the authors generated mice expressing a signalling-deficient TCR ζ-chain (referred to as 6F). Negative selection of double-positive thymocytes was defective in 6F/6F mice, resulting in a peripheral T cell repertoire skewed towards T cells with an activated memory phenotype, presumably owing to a high affinity for self ligands. However, the mice did not develop spontaneous autoimmune disease, which correlated with the increased generation of thymic T_Reg cells. The authors suggest that the attenuation of proximal TCR signalling in 6F/6F mice impairs negative selection but has a compensatory effect on T_Reg cell generation by enhancing FOXP3 expression.