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.