The strength of T cell stimulation determines IL-7 responsiveness, secondary expansion, and lineage commitment of primed human CD4⁺IL-7R^hi T cells

Mouse memory T cell precursors express IL-7 receptor-α (IL-7R), proliferate with homeostatic cytokines and undergo secondary expansions with antigen. Here, we analyzed how the strength of antigenic stimulation regulates IL-7R expression, cytokine responsiveness and expansion potential of DC-primed human CD4⁺ T cells. IL-7R expression on proliferating T cells was highest at intermediate strength of stimulation, and purified CCR7⁺ IL-7R ^hi and CCR7^-IL-7R^lo subsets had characteristics of memory and effector cells, respectively. However, CCR7⁺IL-7R^hi cells generated under different priming conditions had strikingly different properties. Thus, increasing strength of stimulation promoted IL-7 responsiveness that correlated with reduced phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression and enhanced s6 kinase activation, suggesting a tunable IL-7R coupling to P13 kinase-dependent signaling pathways. Furthermore, functional and gene expression analysis revealed that intermediate-stimulated CCR7⁺IL-7R^hi cells were similar to non-polarized central memory cells with high expansion potential. Conversely, high-stimulated CCR7⁺IL-7R^hi cells shared characteristics with circulating pre-Th1 cells and differentiated spontaneously to Th1 effector cells. These results show that the strength of stimulation determines properties of activated IL-7R^hi T cells, and suggest that memory T cell subsets could be derived from CCR7⁺ precursors that received different strengths of stimulation.