An essential role of ITK in T cell migration to the gut during mouse γ-herpesvirus 68 infection

Abstract IL-2-inducible T cell kinase (ITK) is the predominant Tec family kinase in T cells. ITK functions to regulate the magnitude of T cell receptor signaling. Deficiencies in ITK in humans leads to a fatal lymphoproilferative syndrome due to uncontrolled Epstein-Barr virus (EBV) infection. Yet, Itk−/− mice mount protective immune responses against several acute viral infections. To address this dichotomy, we have studied the role of ITK in anti-viral T cell responses to latent γ-herpesvirus infection using mouse γ-herpesvirus 68 (MHV68). Despite a delayed response at D7 post-infection, Itk−/− mice controlled MHV68 replication in the spleen at D14, and WT and Itk−/− mice showed no differences in their viral titers in the spleen during latency. However, MHV68-infected Itk−/− mice (n=11/24) spontaneously developed a severe gastrointestinal pathology after D100 post-infection, whereas WT mice (n=24/24) showed no disease symptoms. Following LPS-induced virus reactivation, Itk−/− mice also showed this pathology in the gut accompanied by a high viral titer in the intestine at various time points during viral latency, while WT mice remained healthy. Consistently, the number of gut-resident T cells were substantially less in Itk−/− mice than WT with or without infection. We also found that P-selectin binding on activated Itk−/− T cells or small molecule inhibitor of ITK (PRN694)-treated WT T cells is greatly impaired. Overall, these data suggest that ITK plays an important role in T cell migration to γ-herpesvirus-infected gut tissue following reactivation from latency.