DeGottardi Maren Q, Okoye Afam A, Vaidya Mukta, Talla Aarthi, Konfe Audrie L, Reyes Matthew D, Clock Joseph A, Duell Derick M, Legasse Alfred W, Sabnis Amit, Park Byung S, Axthelm Michael K, Estes Jacob D, Reiman Keith A, Sekaly Rafick-Pierre, Picker Louis J
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
J Immunol. 2016 Aug 15;197(4):1183-98. doi: 10.4049/jimmunol.1600065. Epub 2016 Jul 18.
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 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 (TEM) 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, 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.
白细胞介素-15（IL-15）被认为是多个系统中T细胞和自然杀伤（NK）细胞稳态的关键调节因子；然而，相对于其他γ链（γc）细胞因子，其在维持外周T细胞和NK细胞群体方面的具体作用在灵长类动物中尚未完全明确。在本文中，我们通过确定恒河猴化的抗IL-15单克隆抗体抑制IL-15对恒河猴T细胞和NK细胞动态的影响来解决这个问题。令人惊讶的是，抗IL-15治疗导致血液和组织中的NK细胞以及CD4(+)和CD8(+)效应记忆T细胞（TEM）迅速耗竭，而对初始或中枢记忆T细胞几乎没有影响。重要的是，虽然NK细胞的耗竭几乎是完全的，并且只要给予抗IL-15治疗就会持续，但TEM的耗竭被大量TEM增殖的开始所抵消，这几乎完全恢复了循环TEM的数量。然而，组织中的TEM仍然显著减少，并且在整个抗IL-15治疗过程中，大多数TEM保持非常高的周转率。在存在IL-15抑制的情况下，TEM在体内对IL-7刺激变得越来越敏感，并且对IL-15抑制的猴子中的TEM进行转录分析发现JAK/STAT信号通路的参与，表明在没有IL-15的情况下，替代性γc细胞因子信号传导可能支持TEM稳态。因此，IL-15在外周NK细胞和TEM的维持中起主要作用。然而，虽然大多数NK细胞群体在没有IL-15的情况下会崩溃，但面对IL-15抑制时，TEM可以通过其他稳态调节因子（最可能是IL-7）的活性得以维持。
