CD38 identifies a hypo‐proliferative IL‐13‐secreting CD4+ T‐cell subset that does not fit into existing naive and memory phenotype paradigms

CD38 is commonly regarded as an activation marker for human T cells. Herein, we show that CD38 expression identifies a hypo‐proliferative CD4+ T‐cell subset that, following TCR stimulation, retains expression of naive cell surface markers including CD45RA, CD62L and CCR7. Hypo‐proliferation was mediated by reduced CD25 up‐regulation upon TCR stimulation compared to CD4+CD38− cells and lack of responsiveness to exogenous IL‐2. Instead, CD4+CD38+ T cells expressed CD127, and hypo‐proliferation was reversed by addition of IL‐7, further associated with increased STAT5 phosphorylation. This phenotype was exacerbated by addition of an agonistic CD38‐binding antibody, suggesting that signaling through CD38 promotes this cell profile. Activated CD4+CD38+ cells had a bias towards IL‐13 secretion, but not other Th2 cytokines such as IL‐4 or IL‐5. In comparison, the CD4+CD38− cells had a clear bias towards secretion of Th1‐associated cytokines IFN‐γ and TNF. The existence of such CD4+CD38+ T cells may play an important role in pathologies such as asthma, which are associated with IL‐13, but not IL‐4 and IL‐5. Coupled with responsiveness to IL‐7 but not IL‐2, and the involvement of CD38 ligation, our results highlight a unique T‐cell subpopulation that does not fit into existing naive and memory cell paradigms.