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-I? 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. A? 2011 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim.