Key Points Myelin-specific CD8 T cells must sense their own IFN-γ to optimally inhibit EAE. IFN-γR−/− CD8s exhibit less IFN-γ, granzyme B, and CD107a and exhibit potential killing defects. IFN-γR−/− CD8s exhibit less CXCR3 and decreased migration to the CNS upon transfer. Investigating the complex cellular interplay controlling immunopathogenic and immunoregulatory responses is critical for understanding multiple sclerosis (MS) and for developing successful immunotherapies. Our group has demonstrated that CNS myelin-specific CD8 T cells unexpectedly harbor immune regulatory capacity in both mouse and human. In particular, PLP178-191–specific CD8 T cells (PLP-CD8) robustly suppress the MS mouse model experimental autoimmune encephalomyelitis. We have recently shown that this depends on PLP-CD8 elaborating IFN-γ and perforin in a coordinated suppression program over time. However, the cellular target and downstream effects of CD8 T cell–derived IFN-γ remains poorly understood. In this study, we show that although wild-type (WT) PLP-CD8 were robustly suppressive in IFN-γR–deficient mice, IFN-γR–deficient PLP-CD8 exhibited suboptimal suppression in WT mice. Compared with WT counterparts, IFN-γR–deficient PLP-CD8 were defective in suppressing disease in IFN-γ–deficient recipients, a scenario in which the only IFN-γ available to WT PLP-CD8 is that which they produce themselves. Further, we found that IFN-γR–deficient PLP-CD8 exhibited altered granzyme/IFN-γ profiles, altered migration in recipients, and deficits in killing capacity in vivo. Collectively, this work suggests that IFN-γ responsiveness allows myelin-specific CD8 T cells to optimally perform autoregulatory function in vivo. These insights may help elucidate future adoptive immunotherapeutic approaches for MS patients.

中文翻译：

---

免疫自动调节 CD8 T 细胞需要 IFN-γ 响应以最佳抑制中枢神经系统自身免疫

关键点髓鞘特异性 CD8 T 细胞必须感知自身的 IFN-γ 以最佳地抑制 EAE。IFN-γR-/- CD8s 表现出较少的 IFN-γ、颗粒酶 B 和 CD107a，并表现出潜在的杀伤缺陷。IFN-γR-/- CD8s 在转移时表现出较少的 CXCR3 和减少向 CNS 的迁移。研究控制免疫病理和免疫调节反应的复杂细胞相互作用对于了解多发性硬化症 (MS) 和开发成功的免疫疗法至关重要。我们的小组已经证明，中枢神经系统髓鞘特异性 CD8 T 细胞出人意料地具有小鼠和人类的免疫调节能力。特别是，PLP178-191 特异性 CD8 T 细胞 (PLP-CD8) 可强力抑制 MS 小鼠模型实验性自身免疫性脑脊髓炎。我们最近表明，随着时间的推移，这取决于 PLP-CD8 在协调抑制程序中详细阐述 IFN-γ 和穿孔素。然而，CD8 T 细胞衍生的 IFN-γ 的细胞靶点和下游效应仍然知之甚少。在这项研究中，我们表明虽然野生型 (WT) PLP-CD8 在 IFN-γR 缺陷小鼠中具有强烈抑制作用，但 IFN-γR 缺陷型 PLP-CD8 在 WT 小鼠中表现出次优抑制。与 WT 对应物相比，IFN-γR 缺陷型 PLP-CD8 在抑制 IFN-γ 缺陷型受体的疾病方面存在缺陷，在这种情况下，WT PLP-CD8 唯一可用的 IFN-γ 是它们自己产生的。此外，我们发现 IFN-γR 缺陷型 PLP-CD8 表现出颗粒酶/IFN-γ 谱的改变、受体迁移的改变以及体内杀伤能力的缺陷。总的来说，这项工作表明 IFN-γ 反应性允许髓鞘特异性 CD8 T 细胞在体内最佳地执行自动调节功能。这些见解可能有助于阐明 MS 患者未来的过继免疫治疗方法。