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 Tand NK cell homeostasis in multiple systems; however, its specific role in maintaining peripheral Tand NK cell populations relative to other γ-chain (γc) 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 γc 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.