Kruppel-like factor 10 regulates innate-like IL-17+CD27−Vγ4+ γδ T cell development

Abstract γδ T cells, an important source of innate IL-17 in mouse and human, are known to act critical contributions to host immune responses. However, certain factors that control their development and homeostasis are poorly elucidated. In the present study, we examined the role of zinc finger transcriptional factor, Kruppel-like factor 10 (KLF10) in the development and homeostasis of IL-17-committed CD27− γδ T (γδ27−-17) cells. We found a selective augmentation of Vγ4+ γδ27− cells, but not of other IL-17-producing αβ T cells, with higher IL-17 production in KLF10-deficient mice. Although either cytokine (IL-7 or IL-1β plus IL-23) or T cell receptor (TCR) stimuli could induce Klf10 on γδ T cells, KLF10 inhibited γδ27− cell responsiveness to IL-7 or IL-1β plus IL-23 but not TCR stimuli. Surprisingly, KLF10-deficient CD127hiVγ4+ γδ27−-17 cells expressed CD5, a stable indicator of TCR strength, higher than their wild-type counterparts. This was also observed in mature (CD24loCD44hi) but not in immature (CD24hiCD44lo) Vγ4+ γδ27− cells from the neonatal thymus of KLF10-deficient mice, with enhanced maturation of these subsets, indicating that KLF10 deficiency promoted high-affinity TCR bearing Vγ4+ γδ27− cell maturation. Finally, mixed bone marrow chimera study indicated that intrinsic KLF10 signaling is mandatory to limit Vγ4+ γδ27−-17 cells. Collectively, these results suggest that the development and homeostasis of innate-like Vγ4+ γδ27−-17 cell are dependent on a transcriptional control by KLF10 which is differently involved in cytokine or TCR signaling.