Postthymic expansion in human CD4 naive T cells defined by expression of functional high-affinity IL-2 receptors

As the thymus involutes with age, the maintenance of peripheral naive T cells in humans becomes strongly dependent on peripheral cell division. However, mechanisms that orchestrate homeostatic division remain unclear. In this study we present evidence that the frequency of naive CD4 T cells that express CD25 (IL-2 receptor a-chain) increases with age on subsets of both CD31+ and CD312 naive CD4 T cells. Analyses of TCR excision circles from sorted subsets indicate that CD25+ naive CD4 T cells have undergone more rounds of homeostatic proliferation than their CD25- counterparts in both the CD31+ and CD312 subsets, indicating that CD25 is a marker of naive CD4 T cells that have preferentially responded to survival signals from self-Ags or cytokines. CD25 expression on CD25- naive CD4 T cells can be induced by IL-7 in vitro in the absence of TCR activation. Although CD25+ naive T cells respond to lower concentrations of IL-2 as compared with their CD25- counterparts, IL-2 responsiveness is further increased in CD312 naive T cells by their expression of the signaling IL-2 receptor b-chain CD122, forming with common g-chain functional high-affinity IL-2 receptors. CD25 plays a role during activation: CD25 + naive T cells stimulated in an APC-dependent manner were shown to produce increased levels of IL-2 as compared with their CD25- counterparts. This study establishes CD25+ naive CD4 T cells, which are further delineated by CD31 expression, as a major functionally distinct immune cell subset in humans that warrants further characterization in health and disease. © 2013 by The American Association of Immunologists, Inc.