Key Points• TCR stimulation increases IL-7 responsiveness.• CD4 1 SPT proliferate more to IL-7 therapy.Interleukin-7 (IL-7) is currently used in clinical trials to augment T-cell counts. Paradoxically, elevated systemic IL-7 found in lymphopenic humans is typically insufficient for CD4 1 T-cell regeneration, and thymopoiesis becomes critical in this process. Here we show that the proliferative effect of IL-7 is more pronounced on CD4 1 CD8 2 thymocytes compared with peripheral CD4 1 T cells. These cells express miR181a at higher levels and respond to lower concentrations of IL-7. As singlepositive CD4 1 thymocytes (CD4 1 SPT ) exit the thymus, they rapidly diminish their proliferation to IL-7 therapy, and this is mediated, at least in part, by major histocompatibility complex class II distribution outside the thymus. Interestingly, increasing T-cell receptor (TCR) stimulation augments IL-7 responsiveness and proliferation of peripheral CD4 1 T cells, whereas failure to stimulate TCR abrogates proliferation induced by IL-7. Finally, we demonstrated that IL-7 enhances the proliferation of CD4 1 T cells that undergo "slow proliferation" in lymphopenic hosts. To date, our results indicate that TCR signaling is a major controlling factor for CD4 responsiveness and proliferation to IL-7 therapy. (Blood. 2013;121(23):4684-4693)
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