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 distinct roles in T cell activation. Nonetheless, deficiencies in either of these pathways lead to seemingly similar phenotypes of impaired T cell homeostasis. A dramatic expansion of CD4(+) peripheral T cells with an activated phenotype 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 complementarity-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 expansion of these cells. In contrast, CTLA-4(-/-) T cells had a diverse and unbiased TCR repertoire, suggestive of a universal, Ag-independent mechanism of activation and expansion. These findings provide insight into the diverse mechanisms controlling T cell homeostasis.