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Absence of the Fyn tyrosine kinase ameliorates T cell induced colitis by inhibiting Th17 differentiation

T helper (Th) 17 cells are a distinct proinflammatory CD4+ T cell subset that protects against fungal and extracellular bacterial infections. Excessive inflammation can be suppressed by Tregs. In autoimmune diseases, such as Crohn’s disease and ulcerative colitis, the Th17/Treg responses are unbalanced. Secretion of IL-17 attracts neutrophils and promotes the production of inflammatory mediators resulting in tissue damage. The Src family tyrosine kinase, Fyn, plays a critical role in regulating IL-17 production. In the absence of Fyn, CD4+ T cells skewed towards the Th17 lineage express RORγt but make little IL-17 and show ectopic expression of the Treg transcription factor FoxP3. We hypothesize that in a T cell transfer model of colitis, the absence of Fyn will decrease IL-17 induced inflammation and reduce disease severity. Rag KO recipients receiving WT CD45Rbhi (naive) CD4 T cells showed characteristic weight loss associated with colitis. In contrast, recipients receiving Fyn −/− CD45Rbhi CD4 T cells maintained their body weight. Mice receiving either WT or Fyn deficient T cells had similar numbers of T cells in the lamina propria, suggesting that the reduced pathology is not due to proliferative defects. Both groups had similar numbers of IFNγ+ (Th1) and RORγt (Th17) positive cells but the Fyn mutant recipients showed a marked decrease in IL-17 secreting T cells. Neutrophil infiltration was highly reduced as well. Furthermore, IL-17 induced genes associated with neutrophil infiltration (S100A8, S100A9), neutrophil chemoattraction (CXCL1, CXCL2), neutrophil homeostasis (CXCL5) and tissue remodeling (MMP9) were all reduced. Together these data suggest Fyn may serve as a novel target for treating Th17 mediated diseases.