Th17 differentiation is the default program for DPP2-deficient T-cell differentiation.

Dipeptidyl peptidase 2 (DPP2) is an N-terminal dipeptidase, required for maintaining lymphocytes in a resting state. Mutant mice with T-cell-specific knock-down (kd) of DPP2 (lck-DPP2 kd) were generated and analyzed for their phenotype. Normal thymocyte development and a modest increase in the proportions of peripheral T cells were observed in these mice compared with littermate controls. Interestingly, the peripheral T cells were hyperactive upon TCR stimulation in vitro, although they did not express any activation markers. Furthermore, CD3-crosslinking in the naïve CD4(+) and CD8(+) T cells of lck-DPP2 kd mice resulted mainly in IL-17 production. Similarly, the mutant T cells secreted primarily IL-17 after in vivo priming and in vitro antigen-specific restimulation. These data suggest that IL-17 production is the default program for T-cell differentiation in the absence of DPP2. Thus, DPP2 seems to impose a threshold for quiescent T cells, preventing them from drifting into cell cycle.