The basis of distinctive IL-2- and IL-15-dependent signaling: Weak CD122-dependent signaling favors CD8+ TCM survival but not TEM development

摘要

Recent work suggests that IL-2 and IL-15 induce distinctive levels of signaling through common receptor subunits and that such varied signaling directs the fate of antigen-activated CD8⁺ T cells. Here we directly examined proximal signaling by IL-2 and IL-15 and CD8⁺ T cell primary and memory responses as a consequence of varied CD122-dependent signaling. Initially, IL-2 and IL-15 induced similar pStat5 and pS6 activation, but these activities were only sustained by IL-2. Transient IL-15-dependent signaling is due to limited expression of IL-15Rα. To investigate the outcome of varied CD122 signaling for CD8⁺ T cell responses in vivo, OT-I T cells were utilized from mouse models where CD122 signals were attenuated by mutations within the cytoplasmic tail of CD122 or intrinsic survival function was provided in the absence of CD122 expression by transgenic Bcl-2. In the absence of CD122 signaling, generally normal primary response occurred, but the primed CD8⁺ T cells were not maintained. In marked contrast, weak CD122 signaling supported development and survival of TCM but not TEM cells. Transgenic expression of Bcl-2 in CD122^−/− CD8⁺ T cells also supported the survival and persistence of TCM cells but did not rescue TEM development. These data indicate that weak CD122 signals readily support TCM development largely through providing survival signals. However, stronger signals, independent of Bcl-2, are required for TEM development. Our findings are consistent with a model whereby low, intermediate, and high CD122 signaling support TCM memory survival, TEM programming, and terminal TEFF differentiation, respectively.