LAT signaling pathology: an “autoimmune” condition without T cell self-reactivity

Partial loss-of-function mutations in several molecules involved in T-cell receptor (TCR) signaling result in inflammation and autoimmunity. How can mutations that reduce TCR signaling output, paradoxically lead to immune pathology? This review summarizes experiments demonstrating that mutations in the linker for activation of T cells (LAT) predispose toward aberrant T cell responses to antigen in the presence of normal thymic selection. In the absence of LAT, antigen-specific T cells give rise to self-perpetuating pro-inflammatory responses and induce the production of autoantibodies independently of TCR engagement. Therefore, some pathological conditions called “autoimmune” might not result from the presence of self-reactive T cells, but from defective mechanisms that normally keep T cell activation in check.