It has recently been documented that survival and homeostasis of peripheral mature T cells depend on self-recognition. Thus, contrary to previous assumptions, naive T cells apparently require a constant subthreshold signal provided by their engagement with self-MHC/peptide ligands to persist in a quiescent state. In a lymphopenic state, this self-MHC/peptide recognition provides a proliferation-inducing signal and leads to T cell expansion until the T cell pool is reestablished to a nearly normal size. Here, we postulate that homeostatic anti-self T cell proliferation may, depending on additional background genes, contribute to systemic autoimmune disease pathogenesis.

Systemic autoimmunity, of which lupus is the prototypic disease, has been extensively investigated, particularly in spontaneous mouse lupus models. Despite key advances in several areas (reviewed in ref. 1), our understanding of the mechanisms leading to a breakdown of tolerance to a wide spectrum of self-molecules remains unclear. Disappointingly, early efforts to demonstrate central T cell tolerance defects in lupus mice, either with regard to deletions of endogenous superantigen-recognizing T cells or to conventional self-peptide–recognizing transgenic antigen receptor–expressing CD4+ or CD8+ cells, were unsuccessful—even in lupus mice with defects in the proapoptotic Fas pathway, by which activated T cells are eventually deleted. Although peripheral T cells of Fas-defective mice show reduced activation-induced cell death, the reasons for the excessive activation of T cells therein has not been identified. We argue below that in this and other seemingly unrelated cases, autoimmune manifestations can result from disturbances in T cell homeostasis that lead to continuous or intermittent T cell stimulation by self-MHC/peptide ligands.