Drug-resistant Th17 cells: culprits in steroid‐refractory Crohn's disease?

Crohn’s disease (CD) is a complex inflammatory bowel disease that affects the entire gastrointestinal tract and afflicts nearly a million adults in the USA alone [1]. Despite recent advances, treatment of CD remains inadequate; the majority of CD patients require surgical intervention due to uncontrolled chronic inflammation [1]. Metaanalyses of genomewide association studies in CD patients reveal at least 143 independent genetic loci that contribute to the disease, with all but 30 of these loci also showing linkage to ulcerative colitis, another common form of inflammatory bowel disease [2]. CD-associated loci also overlap with other autoimmune diseases, particularly psoriasis and ankylosing spondylitis – suggesting common disease physiologies – and are enriched for genes involved in the regulation of IL-17Asecreting CD4 T cells, termed Th17 cells [2]. Th17 cells are a subset of effector CD4 T cells, which differentiate from naive T cells after antigen-dependent activation in the presence of IL-6, together with either TGF-β or IL-1β [3–6]. These cytokines act in concert with general activation signals provided via the T-cell antigen receptor and costimulatory molecules (e.g., CD28) to induce activation of STAT3 and expression of the Th17-specific orphan nuclear receptor, RORγt. In turn, STAT3 and RORγt coordinate Th17 cell differentiation, proliferation and effector cytokine production, namely IL-17A, IL-17F and IL-22 [3,7]. Another STAT3-activating cytokine, IL-23, acts on mature Th17 cells that express the IL-23 receptor to further expand these cells, enforce inflammatory cytokine expression, and prevent expression of antiinflammatory molecules, such as FOXP3 and IL-10 [8,9]. Unlike other CD4 effector T cell subsets, such as IFN-γ-producing Th1 cells or IL-4/-5/-13-expressing Th2 cells, Th17 cells act directly on tissue parenchyma to provoke inflammatory chemokine expression, thereby establishing a feed-forward pathway leading to chronic tissue inflammation. IL-17A-producing Th17 cells are present in the inflamed gut of CD patients where they are enriched relative to their frequency in patient peripheral blood [10]. In addition, Th17 cells home to colonic lamina propria of mice with active experimental colitis, whereas mouse T cells lacking Stat3, Il23r or Rorc, the gene encoding RORγt, fail to induce intestinal inflammation when injected into lymphopenic hosts [3,8,11]. These observations have led to the notion that Th17 cells are involved in CD pathogenesis. Surprisingly, a clinical trial of an IL-17A neutralizing antibody, secukinumab, in CD patients failed to meet efficacy end points. In fact, anti-IL17A treatment actually exacerbated disease activity and led to increased reports of adverse events, such as infection [12]. Although perhaps unexpected, these data are in line with results from the mouse system; unlike Stat3, Il23r and Rorc, Il17a is not a major determinant of pathology in experimental colitis [11,13]. Furthermore, IL17A itself is conspicuously absent from the list of CD-associated loci, unlike many other Th17 signature genes (e.g., IL23R, STAT3, RORC, IL22, and so on) [2]. Thus, whereas Th17 cells per se Mark S Sundrud Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, #2C2, Jupiter, FL 33458, USA Tel.: +1 561 228 2328 msundrud@scripps.edu Drug-resistant Th17 cells: culprits in steroid-refractory Crohn’s disease?