Interferon-alpha drives T cell-mediated immunopathology in the intestine

The ability of interferon (IFN)-alpha to induce autoimmunity and exacerbate Th1 diseases is well known. We have recently described enhanced expression of IFN-alpha in the mucosa of patients with celiac disease (CD), a gluten- sensitive Th1-mediated enteropathy, characterized by villous atrophy and cr ypt cell hyperplasia. Previous studies from this laboratory have shown that T cell activation in explant cultures of human fetal gut can also result i n villous atrophy and crypt cell hyperplasia. We have, therefore, examined changes that take place in explant cultures of human fetal gut after activa tion of T cells with anti-CD3 and/or IFN-alpha. We show that activation of T cells with anti-CD3 alone elicits a small IFN-gamma and TNF-alpha respons e with no tissue injury. Similarly, no changes are seen in explants culture d with IFN-alpha alone. However, addition of IFN-alpha with anti-CD3 result s in enhanced Th1 response and crypt cell hyperplasia. This is associated w ith enhanced phosphorylation of STAT1, STAT3, and Fyn, a Src homology tyros ine kinase, which interacts with both TCR and IFN-alpha signal components. Together these data indicate that IFN-alpha can facilitate activation of Th 1-reactive cells in the gut and drive immunopathology.