The dephosphorylation of FADD at S191 induces an excessive expansion of TCRαβ+ IELs in the intestinal mucosa

Intestinal intraepithelial lymphocytes (IELs) play a crucial role in host defence against pathogens in the intestinal mucosa. The development of intestinal IELs is distinct from peripheral T lymphocytes and remains elusive. Fas-associated protein with death domain (FADD) is important for T cell development in the thymus. Here we describe a novel function of FADD in the IEL development. FADD (S191A), a mouse FADD mutant at Ser191 to Ala mimicking constitutively unphosphorylated FADD, promoted a rapid expansion of TCR alpha beta(+) IELs, not TCR gamma delta(+) IELs. Mechanism investigation indicated that the dephosphorylation of FADD was required for cell activation mainly in TCR alpha beta(+)CD8(+) T cells. Consistently, FADD (S191A) as dephosphorylated FADD led to a high NF-kappa B activation in the TCR-dependent cell expansion. In addition, The FADD (S191A)-induced abnormal IEL populations resulted in the increased incidence and severity of colitis in mice. In summary, FADD signalling is involved in the intestinal IEL development and might be a regulator for intestinal mucosal homeostasis.

Automated summary

This study discovered that FADD plays a significant role in the development of TCRαβ(+) IELs, but not TCRγδ(+) IELs. The dephosphorylation of FADD is crucial for cell activation in TCRαβ(+)CD8(+) T cells and the dephosphorylated FADD promotes high NF-kappa B activation in TCR-dependent cell expansion. Additionally, FADD(S191A) induces abnormal IEL populations and increases the incidence and severity of colitis.