Transcriptional regulation of CD4⁺ T_H  cells that mediate tissue inflammation

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_H ) 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_H  cells and organ-specific autoimmunity. In this review, we provide an overview of the molecular basis of CD4⁺ T_H  cell differentiation and examine how combinatorial expression of transcription factors, which promotes genetic plasticity of CD4⁺ T_H  cells, can contribute to immunological dysfunction of CD4⁺ T_H responses. We also discuss recent studies which highlight the potential of exploiting the genetic plasticity of CD4⁺ T_H  cells in the treatment of autoimmune and other immune-mediated disorders.