Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
J Leukoc Biol. 2018 Dec;104(6):1069-1085. doi: 10.1002/JLB.1RI0418-152RR. Epub 2018 Aug 26.
Acquired and genetic immunodeficiencies have revealed an indispensable role for CD4 T cells in the induction of protective host immune responses against a myriad of microbial pathogens. Influenced by the cytokines present in the microenvironment, activated CD4 T cells may differentiate into several highly-specialized helper subsets defined by the production of distinct signature cytokines tailored to combat diverse classes of pathogens. The process of specification and differentiation is controlled by networks of core, master, and accessory transcription factors, which ensure that CD4 T helper (T ) cell responses mounted against an invading microbe are of the correct specificity and type. However, aberrant activation or inactivation of transcription factors can result in sustained and elevated expression of immune-related genes, leading to chronic activation of CD4 T cells and organ-specific autoimmunity. In this review, we provide an overview of the molecular basis of CD4 T cell differentiation and examine how combinatorial expression of transcription factors, which promotes genetic plasticity of CD4 T cells, can contribute to immunological dysfunction of CD4 T responses. We also discuss recent studies which highlight the potential of exploiting the genetic plasticity of CD4 T cells in the treatment of autoimmune and other immune-mediated disorders.
获得性和遗传性免疫缺陷揭示了 CD4 T 细胞在诱导针对多种微生物病原体的保护性宿主免疫反应中的不可或缺的作用。受微环境中存在的细胞因子的影响，活化的 CD4 T 细胞可分化为几种高度特化的辅助亚群，这些亚群通过产生针对不同类病原体的独特特征细胞因子来定义。特异性和分化的过程受核心、主和辅助转录因子网络的控制，这些转录因子网络可确保针对入侵微生物的 CD4 T 辅助（T）细胞反应具有正确的特异性和类型。然而，转录因子的异常激活或失活可导致免疫相关基因的持续和升高表达，导致 CD4 T 细胞的慢性激活和器官特异性自身免疫。在这篇综述中，我们概述了 CD4 T 细胞分化的分子基础，并探讨了促进 CD4 T 细胞遗传可塑性的转录因子的组合表达如何导致 CD4 T 反应的免疫功能障碍。我们还讨论了最近的研究，这些研究强调了利用 CD4 T 细胞的遗传可塑性来治疗自身免疫和其他免疫介导的疾病的潜力。
