SOCS-1 regulates IL-15–driven homeostatic proliferation of antigen-naive CD8 T cells, limiting their autoimmune potential

Mice that are deficient in suppressor of cytokine signaling–1 (SOCS-1) succumb to neonatal mortality that is associated with extensive cellular infiltration of many tissues. T cells seem to be necessary for disease, which can be alleviated largely by neutralizing interferon-γ. Examining T cell receptor (TCR) specificity shows that even monospecific T cells can mediate disease in SOCS-1–deficient mice, although disease onset is substantially faster with a polyclonal T cell repertoire. A major phenotype of SOCS-1(−/−) mice is the accumulation of CD44(high)CD8(+) peripheral T cells. We show that SOCS-1–deficient CD8, but not CD4, T cells proliferate when transferred into normal (T cell–sufficient) mice, and that this is dependent on two signals: interleukin (IL)-15 and self-ligands that are usually only capable of stimulating homeostatic expansion in T cell–deficient mice. Our findings reveal that SOCS-1 normally down-regulates the capacity of IL-15 to drive activation and proliferation of naive CD8 T cells receiving TCR survival signals from self-ligands. We show that such dysregulated proliferation impairs the deletion of a highly autoreactive subset of CD8 T cells, and increases their potential for autoimmunity. Therefore, impaired deletion of highly autoreactive CD8 T cells, together with uncontrolled activation of naive CD8 T cells by homeostatic survival ligands, may provide a basis for the T cell–mediated disease of SOCS-1(−/−) mice.