Abstract
After emerging from the thymus, naive CD4 T cells circulate through secondary lymphoid tissues, including gut-associated lymphoid tissue of the intestine. The activation of naïve CD4 T cells by antigen-presenting cells offering cognate antigen initiate differentiation programs that lead to the development of highly specialized T helper (Th) cell lineages. Although initially believed that developmental programing of effector T cells such as T helper 1 (Th1) or T helper 2 (Th2) resulted in irreversible commitment to a fixed fate, subsequent studies have demonstrated greater flexibility, or plasticity, in effector T cell stability than originally conceived. This is particularly so for the Th17 subset, differentiation of which is a highly dynamic process with overlapping developmental axes with inducible regulatory T (iTreg), T helper 22 (Th22), and Th1 cells. Accordingly, intermediary stages of Th17 cells are found in various tissues, which co-express lineage-specific transcription factor(s) or cytokine(s) of developmentally related CD4 T cell subsets. A highly specialized tissue like that of the intestine, which harbors the largest immune compartment of the body, adds several layers of complexity to the intricate process of Th differentiation. Due to constant exposure to millions of commensal microbes and periodic exposure to pathogens, the intestinal mucosa maintains a delicate balance between regulatory and effector T cells. It is becoming increasingly clear that equilibrium between tolerogenic and inflammatory axes is maintained in the intestine by shuttling the flexible genetic programming of a developing CD4 T cell along the developmental axis of iTreg, Th17, Th22, and Th1 subsets. Currently, Th17 plasticity remains an unresolved concern in the field of clinical research as targeting Th17 cells to cure immune-mediated disease might also target its related subsets. In this review, we discuss the expanding sphere of Th17 plasticity through its shared developmental axes with related cellular subsets such as Th22, Th1, and iTreg in the context of intestinal inflammation and also examine the molecular and epigenetic features of Th17 cells that mediate these overlapping developmental programs.
Highlights
When an antigen-inexperienced CD4 T cell encounters its cognate antigen in the secondary peripheral lymphoid tissues, it differentiates into T effector cells guided by a microenvironment consisting of a diversity of antigens, antigen-presenting cells (APCs), and other innate immune cells
Contingent on nature of these variable factors, naive CD4 T cell can be programmed to T helper 1 (Th1) cells producing IFNγ; T helper 2 (Th2) cells producing IL-4, IL-5, and IL-13; Th17 cells producing IL-17A/IL-17F; T helper 22 (Th22) cells producing IL-22, or inducible regulatory T cells producing IL-10 [1, 2]
We found that by downregulating SOCS3, IL-1β enhances the amplitude and duration of IL-6-driven pSTAT3 induction and alters the pSTAT3/pSTAT5 balance in developing T cells to enhance Th17 cell development at the expense of iTreg cell development
Summary
When an antigen-inexperienced CD4 T cell encounters its cognate antigen in the secondary peripheral lymphoid tissues, it differentiates into T effector cells guided by a microenvironment consisting of a diversity of antigens, antigen-presenting cells (APCs), and other innate immune cells. Several factors that contribute to the late developmental transition of Th17 precursors to Th1-like cells have been identified, details of how the late developmental axis of Th17 cells overlaps with Th1 cells despite apparent developmental dissimilarities between these two subsets remain to be defined Due to this intrinsic developmental link of Th17 cells with iTreg, Th22, and Th1 cells, a complex dynamic interaction takes place among different cytokine-induced TFs, lineage-specific TFs, and lineage-associated TFs during Th17 differentiation that strongly influences the fate commitment and plasticity of Th17 cells. This indicates a complex, multifactorial decision-making process during Th17 lineage commitment, warranting detailed study of the developmental relationship with related subsets, which will be discussed in this review. The non-cytokine factors that influence Th17 differentiation are as follows: (a) nature of microbial antigen or PAMP, (b) nature of APC, (c) strength of TCR–pMHC interaction, and (d) strength of costimulation
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