We have found two subsets of CD8+ T cells expressing IL-7Rα high and IL-7Rα low with different cell survival responses to IL-7 in peripheral blood of human. Of interest, these IL-7Rα low memory CD8+ T cells that comparably express effector molecules have impaired proliferation and IL-2 production upon TCR stimulation by anti-CD3/CD28 Abs. Treating IL-7Rα low memory CD8+ T cells with anti-CD3/CD28 Abs did not produce IL-2, but comparably expressed IFN-γ and TNF-α, as shown in split anergic cells. Importantly, IL-7Rα low memory CD8+ T cells have reduced calcium flux and subsequent inhibited nuclear translocation of NF-AT1 upon in vitro TCR stimulation by anti-CD3/CD28 Abs, leading to impaired IL-2 production. Moreover, inhibition of IL-2 production and proliferation was not recovered by PMA/ionomycin treatment, suggesting that IL-7Rα low memory CD8+ T cells also have TCR-distal signaling defect of TCR signaling. Interestingly, this anergic status was reversed by exogenous IL-2 stimulation for 10 days, clearly distinct from adaptive tolerance induced by soluble peptide Ag. In conclusion, we firstly showed that specific subset of human CD8+ T cells, IL-7Rα low memory CD8+ T cells, are T-cell clonal anergy in vivo. Based on these findings, we are going to further investigate which mechanisms are in volved in anergic phenotype of human anergic IL-7Rα low memory CD8+ T cells, and eventually, what is the role of these cells in vivo using by humanized mouse.

2014