Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Cell Rep. 2023 Oct 31;42(10):113182. doi: 10.1016/j.celrep.2023.113182. Epub 2023 Sep 29.
Cytotoxic CD4 T cell effectors (ThCTLs) kill virus-infected major histocompatibility complex (MHC) class II cells, contributing to viral clearance. We identify key factors by which influenza A virus infection drives non-cytotoxic CD4 effectors to differentiate into lung tissue-resident ThCTL effectors. We find that CD4 effectors must again recognize cognate antigen on antigen-presenting cells (APCs) within the lungs. Both dendritic cells and B cells are sufficient as APCs, but CD28 co-stimulation is not needed. Optimal generation of ThCTLs requires signals induced by the ongoing infection independent of antigen presentation. Infection-elicited type I interferon (IFN) induces interleukin-15 (IL-15), which, in turn, supports CD4 effector differentiation into ThCTLs. We suggest that these multiple spatial, temporal, and cellular requirements prevent excessive lung ThCTL responses when virus is already cleared but ensure their development when infection persists. This supports a model where continuing infection drives the development of multiple, more differentiated subsets of CD4 effectors by distinct pathways.
细胞毒性 CD4 T 细胞效应物（ThCTLs）可杀死感染病毒的主要组织相容性复合体（MHC）Ⅱ类细胞，有助于清除病毒。我们确定了关键因素，即甲型流感病毒感染如何促使非细胞毒性 CD4 效应物分化为肺组织驻留的 ThCTL 效应物。我们发现，CD4 效应物必须再次识别肺内抗原呈递细胞（APCs）上的同源抗原。树突状细胞和 B 细胞均可作为 APC，但不需要 CD28 共刺激。ThCTL 的最佳产生需要由感染诱导的、与抗原呈递无关的持续感染信号。感染诱导的 I 型干扰素（IFN）诱导白细胞介素 15（IL-15），进而支持 CD4 效应物分化为 ThCTL。我们认为，这些多种空间、时间和细胞要求可防止在病毒已清除时过度产生肺 ThCTL 反应，但在感染持续时确保持续产生。这支持了一种模型，即持续感染通过不同途径驱动多种更分化的 CD4 效应物亚群的发展。
