Effect of Anti–IL-15 Administration on T Cell and NK Cell Homeostasis in Rhesus Macaques

IL-15 has been implicated as a key regulator of T and NK cell homeostasis in multiple systems; however, its specific role in maintaining peripheral T and NK cell populations relative to other gamma-chain (gamma c) cytokines has not been fully defined in primates. In this article, we address this question by determining the effect of IL-15 inhibition with a rhesusized anti-IL-15 mAb on T and NK cell dynamics in rhesus macaques. Strikingly, anti-IL-15 treatment resulted in rapid depletion of NK cells and both CD4(+) and CD8(+) effector memory T cells (T-EM) in blood and tissues, with little to no effect on naive or central memory T cells. Importantly, whereas depletion of NK cells was nearly complete and maintained as long as anti-IL-15 treatment was given, T-EM depletion was countered by the onset of massive T-EM proliferation, which almost completely restored circulating T-EM numbers. Tissue T-EM, however, remained significantly reduced, and most T-EM maintained very high turnover throughout anti-IL-15 treatment. In the presence of IL-15 inhibition, T-EM became increasingly more sensitive to IL-7 stimulation in vivo, and transcriptional analysis of T-EM in IL-15-inhibited monkeys revealed engagement of the JAK/STAT signaling pathway, suggesting alternative gamma c cytokine signaling may support T-EM homeostasis in the absence of IL-15. Thus, IL-15 plays a major role in peripheral maintenance of NK cells and T-EM. However, whereas most NK cell populations collapse in the absence of IL-15, T-EM can be maintained in the face of IL-15 inhibition by the activity of other homeostatic regulators, most likely IL-7.