Deciphering the role of gammaherpesvirus in shaping IBD profiles through advanced immunophenotyping

Inflammatory bowel disease (IBD) are chronic immune-mediated disease with perplexing heterogeneity in clinical manifestation and response to treatment. While the molecular basis of this heterogeneity remains ill defined, epidemiological studies have highlighted potential contribution of Epstein-Barr virus infection in IBD development. Establishing a causal link and deciphering the underlying mechanisms is challenging in humans because of the existence of confounding factors and model limitations. In this study, we used dextran sulfate sodium (DSS)-induced colitis and a mouse gammaherpesvirus (γHV), Murid herpesvirus 4 (MuHV-4) to explore whether γHV infection could drive specific intestinal immune responses, representing a risk factor for the subsequent development or exacerbation of IBD. Immunophenotyping of lamina propria leucocytes using advanced spectral flow cytometry and multiparametric confocal microscopy showed a marked increase in T cell infiltration in the colon of MuHV-4 infected mice during DSS-induced colitis. These T cells displayed an effector memory phenotype with a unique activation profile characterized by co-expression of activation markers such as Sca-1, Ly6C, KLRG1 and CD11c and by enhanced proliferative and cytotoxic properties. Interestingly, this infiltration of activated T cells into the colon was associated with a significant accumulation of CXCL9-secreting monocytes, potentially playing a key role in the attraction and functional polarization of these T cell subsets. Dissecting the importance of these cellular interactions during DSS-induced colitis could help to understand whether and how γHV influences the development of some IBD subtypes and could guide the design of personalized therapies based on an identified specific immune signature.