T cell homeostasis in tolerance and immunity

Abstract: The size of the peripheral T cell pool is remarkably stable throughout life, reflecting pre-cise regulation of cellular survival, proliferation, and apoptosis. Homeostatic proliferation refers to the process by which T cells spontaneously prolif-erate in a lymphopenic host. The critical signals driving this expansion are “space, ” contact with self-major histocompatibility complex (MHC)/pep-tide complexes, and cytokine stimulation. A num-ber of studies have delineated an association be-tween T cell lymphopenia, compensatory homeo-static expansion, and the development of diverse autoimmune syndromes. In the nonobese diabetic mouse model of type 1 diabetes, lymphopenia-in-duced homeostatic expansion fuels the generation of islet-specific T cells. Excess interleukin-21 facil-itates T cell cycling but limited survival, resulting in recurrent stimulation of T cells specific for self-peptide/MHC complexes. Indeed, data from sev-eral experimental models of autoimmunity indicate that a full T cell compartment restrains homeo-static expansion of self-reactive cells that could otherwise dominate the repertoire. This review de-scribes the mechanisms that govern T cell homeo-static expansion and outlines the evidence that lym-phopenia presents a risk for development of auto