Trends in Pharmacological Sciences
ReviewTargeting Th17 cells in autoimmune diseases
Section snippets
Regulation and function of Th17 cells
CD4+ T helper (Th) cells regulate immunity and inflammation through antigen-dependent activation and cytokine-dependent differentiation into functionally distinct effector and regulatory T cell subsets. Th17 cells are a uniquely proinflammatory lineage of effector/memory Th cells first identified by (and named for) production of IL-17A (hereafter referred to as IL-17). The prominent role of Th17 cells in inflammation and autoimmunity was quickly established when IL-17-producing Th17 cells were
Th17 cells in immunity and inflammation
Th17 cells accumulate at mucosal surfaces of the gut, skin, and lung, where they regulate protective immunity against a variety of bacteria, including Mycobacteria tuberculosis, Klebsiella pneumonia, Citrobacter rodentium, and Pneumocystis carinii. In addition, Th17 cells are likely to be the primary T cell subset responsible for control of pathogenic fungi, such as Candida albicans 6, 7. The role of Th17 cells in protective immune responses is best illustrated by hyper-IgE syndrome (HIES), an
RORγt in immunity and Th17 cell differentiation
ROR is a member of the nuclear receptor superfamily containing an N-terminal A/B domain, a DNA-binding domain (DBD), a hinge region (D), a ligand-binding domain (LBD), and a variable C-terminal region. In most nuclear receptors, ligand binding to the LBD induces a conformation change, recruitment of transcriptional co-activators, and activation of transcriptional activity. There are three members of the ROR family: RORα (or RORA), RORβ (or RORB), and RORγ (or RORC) [23]. Two different forms of
Development of RORγt small molecule inverse agonists
The RORγt LBD is an ideal domain to target via small molecules. Small molecules targeting RORs come in at least two types: inverse agonists, which block ROR-dependent transcriptional activity; and agonists, which enhance the transactivation of RORs [29]. To identify RORγt inverse agonists, Dan Littman and colleagues developed Drosophila S2 cells stably expressing both a GAL4 DBD/RORγ LBD fusion protein and the activation domain of the general transcriptional activator VP16. Induction of RORγ
Diverse biochemistry of RORγt inverse agonists
All published RORγt inverse agonists inhibit Th17 cell differentiation, as defined solely by IL-17 expression. Crystal structure analyses demonstrate that digoxin or SR1001 directly bind the LBD of RORγt 32, 36. However, it is unknown whether subtle differences in compound binding differentially influence RORγt transcriptional activity; indirect evidence suggests that not all RORγt inverse agonists share the same biological profile. For example, SR1001 has no effect on expression of forkhead
IL-23
IL-23 is a vital checkpoint in the generation, maintenance, and activation of pathogenic Th17 cells 1, 26, 42 (Figure 2). This is largely attributable to the fact that only proinflammatory Th17 cells express the IL-23 receptor (IL-23R). IL-23 is a heterodimeric, IL-12-related proinflammatory cytokine composed of the shared IL-12/23 p40 subunit and a unique p19 subunit. The central role of IL-23 in autoimmune pathogenesis is highlighted by studies showing that mice deficient in IL-23 (p19−/−),
Concluding remarks
Th17 cells are key effectors of autoimmune disease. However, antibodies targeting IL-17 or IL-17R have shown clinical efficacy in psoriasis, but not in many other indications in which Th17 cells are implicated in disease pathogenesis (e.g., RA, IBD). Targeting Th17 cells themselves, as opposed to a single effector cytokine, holds promise in maximizing patient benefit by impacting multiple inflammatory cytokines (IL-17, IL-17F, IL-22, IL-26, and GM-CSF) that are likely to act synergistically to
Acknowledgments
We thank Gary Bohnert for drawing the molecule structure of RORγt inverse agonists.
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