IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation

The interferon-inducible transmembrane (Ifitm/Fragilis) genes encode homologous proteins that are induced by IFNs. Here, we show that IFITM proteins regulate murine CD4 ⁺ Th cell differentiation. Ifitm2 and Ifitm3 are expressed in wild-type (WT) CD4 ⁺ T cells. On activation, Ifitm3 was downregulated and Ifitm2 was upregulated. Resting Ifitm-family-deficient CD4 ⁺ T cells had higher expression of Th1-associated genes than WT and purified naive Ifitm-family-deficient CD4 ⁺ T cells differentiated more efficiently to Th1, whereas Th2 differentiation was inhibited. Ifitm-family-deficient mice, but not Ifitm3-deficient mice, were less susceptible than WT to induction of allergic airways disease, with a weaker Th2 response and less severe disease and lower Il4 but higher Ifng expression and IL-27 secretion. Thus, the Ifitm family is important in adaptive immunity, influencing Th1/Th2 polarization, and Th2 immunopathology.