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

Abstract

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.

The IFITM protein family in adaptive immunity

“…13 In naive CD4 + T cells, RNA sequencing showed that expression of Ifitm3 was rapidly down-regulated during the first 24 hr after activation by anti-CD3/CD28 ligation in T helper type 0 (Th0), Th1 and Th2 culture conditions, whereas Ifitm2 was up-regulated and its expression continued to rise for the first 3 days after activation and levels of Ifitm1 were low and were not changed by TCR signalling. 13 In contrast, expression analysis of IFITM3 protein by Western blotting on naive CD8 + and CD4 + T cells following anti-CD3/CD28 activation demonstrated that IFITM3 protein is up-regulated by day 3 following T-cell activation. 7 This up-regulation was independent of interferon signalling, as naive T cells purified from mice which constitutively lack interferon-c (IFN-c), the IFN-a receptor, or the transcription factors IIrf3 and Irf7, which drive interferon-induced up-regulation of Ifitm3, all showed increased expression of IFITM3 protein 2 days after TCR ligation.…”

“…Several distinct functions have been associated with different IFITM family members, including germ cell specification (IFITM1-IFITM3), [14][15][16]23,24 osteoblast function and bone mineralization (IFITM5), [25][26][27][28][29] and immune functions (IFITM1-3, IFITM6), 7,8,13,[30][31][32][33][34][35][36][37][38] in addition to their roles as virus-restriction factors (IFITM1-3, murine IFITM6). The IFITM proteins have also been described to play a role in cell cycle control and apoptosis and their dysregulated expression, over-expression or mutation can be associated with colon cancers and metabolic dysregulation.…”

“…7,11,13,37 Expression of Ifitm2 and Ifitm3 are regulated by TCR signalling. 13 In naive CD4 + T cells, RNA sequencing showed that expression of Ifitm3 was rapidly down-regulated during the first 24 hr after activation by anti-CD3/CD28 ligation in T helper type 0 (Th0), Th1 and Th2 culture conditions, whereas Ifitm2 was up-regulated and its expression continued to rise for the first 3 days after activation and levels of Ifitm1 were low and were not changed by TCR signalling. 13 In contrast, expression analysis of IFITM3 protein by Western blotting on naive CD8 + and CD4 + T cells following anti-CD3/CD28 activation demonstrated that IFITM3 protein is up-regulated by day 3 following T-cell activation.…”

“…7,8 Interestingly, IFITM3 is also constitutively expressed in tissue-resident T cells in lung and airways, and also spleen, skin and brain, suggesting that it promotes their survival at these sites of potential viral infection. 8,12,13,37,53,69 Hence, several in vivo and in vitro studies have demonstrated the importance of IFITM3 in immunity to viral infection, by enhancing survival and viral resistance of immune effector populations, but these studies did not demonstrate an additional direct function of the IFITM proteins in the immune function of T cells or dendritic cells.…”

“…7,8 Ifitm genes are targets of transcriptional repression by Bcl6, and have been shown to be targets of Wnt/b-catenin and Hedgehog (Hh) signal transduction [9][10][11][12] ; and in murine T cells IFITM2 and IFITM3 expression is regulated by T-cell receptor (TCR) signal transduction. 7,9,13 In humans, five IFITM genes have been identified, which are located on chromosome 11, whereas in mice there are seven Ifitm genes, six of which are located on chromosome 7, and one on chromosome 16 (illustrated in Fig. 1a).…”