Regulation of naive T cell homeostasis in the periphery and the potential relevance for the development of autoimmunity. Positive and negative selection in the thymus creates a repertoire of T cells with a broad spectrum of affinities to self, from low self-affinity (just strong enough to escape from death by neglect) to comparatively high self-affinity, which is, however, not strong enough to undergo negative selection. In a T cell–sufficient individual, the bulk of naive T cells needs continuous signals by self-MHC/self-peptide complexes to survive in a quiescent state. How the presence of surrounding T cells prevents naive T cells from uncontrolled proliferation is currently unknown. Competition for soluble stimulatory factors (labeled “1” in figure), for contact with self-MHC/self-peptide complexes (labeled “2”), or a direct inhibitory effect between T cells themselves (labeled “3”) are possible mechanisms. Even while resting, a certain degree of T cell receptor engagement is measurable. Reduction of T cell numbers leads to spontaneous homeostatic T cell expansion, either by increased availability of stimulatory factors (labeled “1,” “2”) or by reduction of inhibitory impulses (labeled “3”). Homeostasis-driven proliferation leads to upregulation of some activated/memory markers. This proliferation usually occurs innocuously, without harm to normal individuals under physiologic circumstances. Either through constitutive T cell depletion or repeated episodes of T cell depletion, a T cell repertoire might be skewed to more T cells with high self-affinity. In this scenario, when homeostatic T cell expansion occurs, such cells, in conjunction with the appropriate genetic background and/or coexisting inflammation, might be overstimulated. In some models, such T cells have been shown to hyper-respond and acquire effector function. This provides the basis for the development of autoimmunity