Postthymic Expansion in Human CD4 Naive T Cells Defined by Expression of Functional High-Affinity IL-2 Receptors
Pekalski ML., Ferreira RC., Coulson RMR., Cutler AJ., Guo H., Smyth DJ., Downes K., Dendrou CA., Castro Dopico X., Esposito L., Coleman G., Stevens HE., Nutland S., Walker NM., Guy C., Dunger DB., Wallace C., Tree TIM., Todd JA., Wicker LS.
Abstract 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 α-chain) increases with age on subsets of both CD31+ and CD31− 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 CD31− 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 CD31− naive T cells by their expression of the signaling IL-2 receptor β-chain CD122, forming with common γ-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.