Department of Pathology, University of California, San Francisco, CA 94143;
The Kennedy Institute of Rheumatology, University of Oxford, OX3 7FY Oxford, United Kingdom.
Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11585-11590. doi: 10.1073/pnas.1804556115. Epub 2018 Oct 22.
The cytokine IFN-γ is a critical regulator of immune system development and function. Almost all leukocytes express the receptor for IFN-γ, yet each cell type elicits a different response to this cytokine. Cell type-specific effects of IFN-γ make it difficult to predict the outcomes of the systemic IFN-γ blockade and limit its clinical application, despite many years of research. To better understand the cell-cell interactions and cofactors that specify IFN-γ functions, we focused on the function of IFN-γ on CD8 T cell differentiation. We demonstrated that during bacterial infection, IFN-γ is a dominant paracrine trigger that skews CD8 T cell differentiation toward memory. This skewing is preferentially driven by contact-dependent T cell-T cell (T-T) interactions and the localized IFN-γ secretion among activated CD8 T cells in a unique splenic microenvironment, and is less sensitive to concurrent IFN-γ production by other immune cell populations such as natural killer (NK) cells. Modulation of CD8 T cell differentiation by IFN-γ relies on a nonconventional IFN-γ outcome that occurs specifically within 24 hours following infection. This is driven by IFN-γ costimulation by integrins at T-T synapses, and leads to synergistic phosphorylation of the proximal STAT1 molecule and accelerated IL-2 receptor down-regulation. This study provides evidence of the importance of context-dependent cytokine signaling and gives another example of how cell clusters and the microenvironment drive unique biology.
细胞因子 IFN-γ 是免疫系统发育和功能的关键调节剂。几乎所有白细胞都表达 IFN-γ 的受体，但每种细胞类型对这种细胞因子的反应都不同。IFN-γ 的细胞类型特异性作用使得很难预测全身性 IFN-γ 阻断的结果，并限制了其临床应用，尽管已经进行了多年的研究。为了更好地了解细胞间相互作用和决定 IFN-γ 功能的协同因子，我们专注于 IFN-γ 对 CD8 T 细胞分化的功能。我们证明，在细菌感染期间，IFN-γ 是一种优势旁分泌触发因子，使 CD8 T 细胞向记忆细胞分化。这种倾斜主要是由依赖接触的 T 细胞-T 细胞（T-T）相互作用和在独特的脾微环境中激活的 CD8 T 细胞之间局部 IFN-γ 分泌驱动的，并且对其他免疫细胞群体（如自然杀伤（NK）细胞）同时产生 IFN-γ的敏感性较低。IFN-γ 对 CD8 T 细胞分化的调节依赖于一种非传统的 IFN-γ 结果，该结果仅在感染后 24 小时内发生。这是由 T-T 突触上整合素对 IFN-γ 的共刺激驱动的，并导致近端 STAT1 分子的协同磷酸化和 IL-2 受体的快速下调。这项研究提供了依赖于上下文的细胞因子信号的重要性的证据，并提供了另一个例子，说明细胞簇和微环境如何驱动独特的生物学。
