IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages

Abstract

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…Therefore, we hypothesized a role of TLR2-expressing LC for polarizing Th17 immune responses and investigated their potential to induce IL-17. In this study we show that peptidoglycan (PGN)-stimulated MoLC secreted IL-6, IL-1b, IL-23, and TGF-b Blocking of TLR2 by specific antibody inhibited IL-6, IL- To date, IL-6 and TGF-b are prominent cytokine candidates for polarization of naive Th cells into Th17 cells, whereas IL-23 is discussed for Th17 outgrowth of already differentiated cells [5][6][7]26]. In human skin, among other cytokines IL-6 is produced by LC upon microbial stimulation by PGN and other TLR2 agonists [23].…”

“…Upon stimulation Th17 cells acquire the capacity to produce the inflammatory cytokine IL-17 [4]. Recent reports demonstrate that Th17 cells are involved in processes of defence against extracellular bacteria and fungi, cancer and autoimmunity [5][6][7]. Furthermore, it was observed that the Th2-derived IL-17E, which is a member of the IL-17 cytokine family (A-F), plays a role in boosting allergic reactions by induction of IL-4, IL-5, and IL-13.…”

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

“…1A). Interestingly, Th17-related cytokines such as IL-17, IL-6 and GM-CSF [12,29], were also significantly higher in IL-10 À/À mice, when compared with WT control animals, indicating that IL-10 À/À mice not only develop a Th1 immune response, but also an antigen-specific Th17 response after T. muris infection (Fig. 1A).…”

“…The Th2 immune response with T cells producing IL-4, IL-5 and IL-13 provides immunity to helminths [2]. Th17 cells produce cytokines like IL-17, IL-22 and mediate immunity to extracellular bacteria and fungi, but are also responsible for autoimmunity and inflammation [12,13]. Development of naïve T cells to Th17 cells requires the presence of IL-6, TGF-b1 and the transcription factor RORgt [14][15][16][17].…”

Identification and characterization of multiple splice forms of the human interleukin-23 receptor α chain in mitogen-activated leukocytes

“…In Th17 cell development, native CD4 þ T cells are activated by IL-6 from mature dendritic cells, which acts together with activated TGF-b to induce expression of the retinoic orphan receptor RORgt and upregulate IL-23R, thus making them competent for IL-17 production through STAT 3 signalling. 6,7 The importance of IL-23R in controlling innate immunity through Th17 cells may underscore why the IL23R gene also has been demonstrated to confer susceptibility to several autoimmune diseases, including psoriasis, 8,9 ankylosing spondylitis, 10 multiple sclerosis [11][12][13] and inflammatory bowel diseases (both Crohn's disease and/or ulcerative colitis). 14,15 In addition, a separate study by the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium found evidence to suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.…”