TH17 cell heterogeneity and its role in tissue inflammation

Abstract

Since their discovery almost two decades ago, interleukin-17-producing CD4⁺ T cells (T_H17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders. In addition, T_H17 cells have been found to play an important role in tissue homeostasis, especially in the intestinal mucosa. Recently, the use of single-cell technologies, along with fate mapping and various mutant mouse models, has led to substantial progress in the understanding of T_H17 cell heterogeneity in tissues and of T_H17 cell plasticity leading to alternative T cell states and differing functions. In this Review, we discuss the heterogeneity of T_H17 cells and the role of this heterogeneity in diverse functions of T_H17 cells from homeostasis to tissue inflammation. In addition, we discuss T_H17 cell plasticity and its incorporation into the current understanding of T cell subsets and alternative views on the role of T_H17 cells in autoimmune and inflammatory diseases.

Figure 1:. Th17 cell heterogeneity in intestinal homeostasis

Schematic depicting the role of intestinal Th17 cells in intestinal homeostasis. Specific microbiota, including epithelial-adhering bacteria, induce the differentiation of antigen-specific, naïve CD4⁺ T cells to Th17 cells [71]. By differences in the APC or intra-tissue plasticity, the Th17-polarized T cell clones can give rise to different Th17 subpopulations. One subpopulation includes SLAMF6⁺ stem-like Th17 cells that circulate through lymphoid organs and intestinal tissues and are maintained by the gut microbiota [38]. Effector Th17 cells express high levels of IL-17A, IL-17F, and IL-22 which directly support the barrier function of the intestinal epithelium by enhancing the expression of tight junction proteins and antimicrobial peptides [70, 71]. In addition, intestinal IL-17A has been shown to support social behavior by directly signaling through neurons [82]. Tfh-like Th17 cells induce IgA-production by B cells in mesenteric lymph nodes and Peyer’s patches, thereby supporting microbial homeostasis [26, 38].

Figure 2:. Drivers of tissue-specific signatures of immune cells

Tissue immune cells, including macrophages [107], Treg cells [106] and Th17 cells [38], acquire specific transcriptomic signatures depending on the tissue they are resident in. Indirect (outer circle) and direct (inner circle) factors likely shape these tissue-specific signatures of immune cells. Indirect factors include the space and location of the cell in the tissue, the interactions with tissue cells, and the presence of microorganisms. Direct factors influencing the tissue signatures are oxygen availability in the tissue, present nutrients and metabolites shaping the cell metabolism, and hormones and growth factors that directly bind and signal through their receptors on the immune cells.

Figure 3:. Th1 and Th17 cell subsets in tolerance and inflammation

CD4⁺ T helper cell subsets, including Th1 cells, Th2 cells, and Th17 cells, are characterized by the expression of signature cytokines and master transcription factors. In addition, during inflammation or resolution of inflammation common pro-inflammatory or regulatory modules can be induced in the cells, as shown for Th1 [173] and Th17 cells [53]. IL-23 and IL-1ß induce a common pro-inflammatory module including Bhlhe40, GM-CSF, IFNγ, and CXCR6 [33, 38, 177]. In contrast, IL-27 induces the expression of a common regulatory module that includes anti-inflammatory molecules such as IL-10 and co-inhibitory molecules [105, 180]. The color coding and positioning of the cell types represents pTh17 cells as an intermediate cell type between npTh17 cells and Th1 cells [60]. pTh17= pathogenic Th17 cell, npTh17= non-pathogenic Th17 cell.

Figure 4:. Th17 cells in intestinal and extra-intestinal autoimmunity

Schematic of the role of intestinal Th17 cells in autoimmune tissue inflammation in the intestine and in extra-intestinal organs. Specific microbiota induce the generation of intestinal Th17 cells [71]. Some of the Th17 cells can give rise to the SLAMF6⁺ stem-like Th17 subpopulation that circulates through lymphoid organs and intestinal tissues [38]. Under the presence of IL-23 signaling and presentation of auto-antigens by APCs in the spleen, the SLAMF6⁺ population can give rise to CXCR6⁺ pathogenic Th17 cells that express high levels of GM-CSF and IFNγ. This CXCR6⁺ pathogenic Th17 population migrates directly to the inflamed tissue where it mediates autoimmune tissue inflammation. In the intestine diverse factors promote the generation of pathogenic Th17 cells that express high levels of IL-17A, GM-CSF, and IFNγ and drive tissue inflammation. High salt, LCFAs, and saturated fatty acids from the diet and the microbiota and the expression and secretion of SAAs and reactive oxygen species (ROS) by intestinal epithelial cells favor a pathogenic phenotype in Th17 cells [37, 71]. In addition, the secretion of pro-inflammatory cytokines IL-1β and IL-23 by myeloid cells differentiates pathogenic Th17 cells. The pathogenic Th17 population is regulated by a pool of intestinal Treg cells that are dependent on the transcription factor c-MAF [43]. In Helicobacter hepaticus- dependent intestinal colitis, the induction of the H. hepaticus-specific Treg cells is mediated by a recently identified population of RORγt⁺ APCs, that are equipped to release TGF-β [–183].