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

Abstract

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 (γc) cytokines has not been fully defined in primates. Here, 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 (TEM) in blood and tissues, with little to no effect on naïve 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, TEM depletion was countered by the onset of massive TEM proliferation, which almost completely restored circulating TEM numbers. Tissue TEM, however, remained significantly reduced, and most TEM maintained very high turnover throughout anti-IL-15 treatment. In the presence of IL-15 inhibition, TEM became increasingly more sensitive to IL-7 stimulation in vivo, and transcriptional analysis of TEM in IL-15-inhibited monkeys revealed engagement of the JAK/STAT signaling pathway, suggesting alternative γc cytokine signaling may support TEM homeostasis in the absence of IL-15. Thus, IL-15 plays a major role in peripheral maintenance of NK cells and TEM. However, whereas most NK cell populations collapse in the absence of IL-15, TEM can be maintained in the face of IL-15 inhibition by the activity of other homeostatic regulators, most likely IL-7.

γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming

“…The effects of γδT cells were independent of IL‐17A, but contingent on IL‐15 and VEGF. This is consistent with an emerging body of evidence that suggests that both VEGF and IL‐15 modulate effector T‐cell differentiation . Our work thus provides mechanistic understanding of the complex functional phenotype and interactions of γδT cells in SH and identifies targets for therapeutic intervention.…”

“…This is consistent with an emerging body of evidence that suggests that both VEGF and IL-15 modulate effector T-cell differentiation. (23)(24)(25)(26)(27)48,49) Our work thus provides mechanistic understanding of the complex functional phenotype and interactions of γδT cells in SH and identifies targets for therapeutic intervention. However, the clinical implications of this study are tempered by the fact that human γδT cells have distinct subset composition compared to mice.…”

Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice

“…We then considered deleting IL‐15 because the role of IL‐15 in reactivating T MEM in the context of menopause has not been defined. A global knockout or antibody‐mediated depletion of IL‐15 was rejected because this cytokine plays an important role in NK cell homeostasis that would make interpretation of the results questionable and because anti‐IL‐15 antibodies have been shown to produce adverse neurological effects . Further, IL‐15 has been shown to directly regulate osteoclastogenesis and mineralization by osteoblasts .…”

Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis

“…This is in contrast with a recent report showing that a rhesusized anti-IL-15 monoclonal antibody could also decrease circulating CD4 and CD8 TEM when administered to rhesus macaques. 40 It is possible that this discrepancy is related to a different choice of markers to identify TEM cells between the 2 reports. Nevertheless, CALY-002 was very potent in cynomolgus monkeys, with almost maximal effect at the 0.1 mg/kg dose.…”

“…Administration of anti-IL-15 antibodies to cynomolgus or rhesus monkeys was shown to induce a decrease of circulating NK cell numbers within a 2-week period. 39,40 Since CALY-002 is able to bind and neutralize cynomolgus monkey IL-15 (Tables 1 and 2), we intravenously (i.v.) administered a single injection of CALY-002 at 3 different doses (0.1 mg/kg, 1 mg/kg and 10 mg/kg) to groups of cynomolgus monkeys.…”