These authors contributed equally.1 The maintenance of a diverse, naïve T cell repertoire arising from the thymus (recent thymic emigrants: RTEs) is critical for health 1 . Recent studies have reported a unique naïve CD4 + T cell subset in neonates and early childhood characterized by IL-8 production 2,3 . Here we demonstrate that IL-8 production is a characteristic feature of RTEs in adults, children and neonates and that a hallmark of these cells is the expression of complement receptor 2 (CR2) and the preferential production of IL-8 after activation. Although decreasing in number with age due to thymic involution and homeostatic expansion of naïve CD4 + T cell in humans 4 , CR2 + RTEs persist into old age, have the highest levels of T cell receptor excision circles (TRECs), co-express complement receptor 1 (CR1), TLR1 and produce IL-8 upon TCR stimulation. We have observed these phenotypes in the vast majority of cord blood naïve CD4 + T cells and in newly-generated naïve T cells appearing during reconstitution of the immune system in adults depleted of T cells through treatment for multiple sclerosis. A memory subset of CR2 + CD4 + T cells expressing high levels of CR1 and producing IL-8 following activation was also discovered, consistent with the hypothesis that RTE-specific gene expression confers a functional competence retained by particular memory T cells possibly because of their complement-dependent reactivity to pathogens. We suggest that assessing CR2 expression on naïve CD4 + T cells will give a measure of thymic function during aging of the immune system and in a number of clinical situations including bone marrow transplantation 5 , HIV infection 6 , and immune reconstitution following immune depletion 7 or chemotherapy 8 .Thymic involution decreases naïve CD4 + T cell production with age in humans and is compensated for by the homeostatic expansion of naïve cells that have emigrated from the thymus earlier in life 1,4 . Naïve T cells that have undergone decades of homeostatic expansion show reduced T cell receptor diversity that potentially negatively impacts host defence 9 . CD31 (PECAM-1) expression identifies cells that have divided more often in the periphery (CD31 − ) from those that have not (CD31 + ), although CD31 + T cells still divide with age as evidenced by the dilution of TRECs 10 and, therefore, better markers of undivided naïve T cells are clearly needed 11 . As we and others have reported 12,13 , CD25 is an additional marker of naïve T cells that have expanded in the periphery. CD31 + CD25 − naïve CD4 + T cells predominate at birth and contain the highest content of TRECs as compared to their CD31 − and CD25 + counterparts 12 .Here, we assessed the heterogeneity of four naïve CD4 + T cell subsets defined by CD31 and CD25 expression in neonates and adults in a population study of 391 donors ( Fig. 1a, Supplementary Fig. 1a). CD31 + CD25 − naïve CD4 + T cells decreased with age and this decrease was compensated for by 2 the homeostatic expansion of three subsets of naïve T cells:...