Cutting edge: Two distinct mechanisms lead to impaired T cell homeostasis in Janus kinase 3-and CTLA-4-deficient mice

Cytokine receptor signaling and costimulatory receptor signaling play disti nct roles in T cell activation. Nonetheless, deficiencies in either of thes e pathways lead to seemingly similar phenotypes of impaired T cell homeosta sis. A dramatic expansion of CD4(+) peripheral T cells with an activated ph enotype has been observed in both Janus kinase (Jak) 3-deficient and CTLA-4 -deficient mice. Despite these similarities, the mechanisms driving T cell expansion may be distinct. To address this possibility, we examined the TCR repertoire of peripheral T cells in Jak3(-/-) and CTLA-4(-/-) mice using c omplementarity-determining region 3 spectratype analysis. Interestingly, a restricted and highly biased TCR repertoire was observed in the Jak3(-/-) T cells, strongly supporting a role for foreign Ag in the activation and exp ansion of these cells. In contrast, CTLA-4(-/-) T cells had a diverse and u nbiased TCR repertoire, suggestive of a universal, Ag-independent mechanism of activation and expansion. These findings provide insight into the diver se mechanisms controlling T cell homeostasis.