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The role of Butyrophilin-like molecule 1 in intestinal epithelial cell-T cell interactions and immune surveillance

Final Report Summary - BUTIES (The role of Butyrophilin-like molecule 1 in intestinal epithelial cell-T cell interactions and immune surveillance)

Project context and objectives

The gut is a site of chronic immune stimulation where the control of tissue inflammation and stress responses is particularly challenging. In this arena, functional interactions of epithelial cells with intraepithelial T lymphocytes (IEL) are probably essential to maintain immune surveillance. However, few molecules regulating such interactions have been identified. Skint1, a novel immunoglobulin (Ig)-supergene family member restricted to thymic and skin epithelia was recently shown to specify the murine epidermal IEL repertoire. Reasoning that Skint1-related molecules might regulate other IEL compartments, we identified the buytrophilin-like (Btnl) family as conspicuously similar to Skint1, and sharing many features with the B7 family of T cell costimulators. Moreover, the Btnl family of molecules is conserved in mice and humans, is expressed from the extended MHC locus, and includes members of the Immunoglobulin (Ig) superfamily. For these reasons, we undertook to characterise the role of Btnl1 in the gut and to address its relevance in immune regulation. As Btnl1 can be expressed on the cell surface, we attempted to identify a putative receptor on IEL that might regulate IEL-epithelial cell interactions. Lastly, we wanted to define a role for Btnl1 in immune surveillance in the gut.

Work performed and main results

We found that in vivo Btnl1 is largely restricted to intestinal epithelial cells (IEC). It is mostly retained intracellularly, but can be expressed at the enterocyte surface when apposed to IEL, and this translocation depends on inflammatory mediators from IEL. Using a novel culture system for IEL, we showed that Btnl1 selectively suppresses pro-inflammatory epithelial cell responses to cytokines produced by activated IEL, while increasing expression of MHC class II. Expression of Btnl1 down-modulates sustained activation of the JNK signalling pathway, which has consequences for the survival of the cell. These findings, added to emerging genetic data, highlight Btnl1 as a novel and important attenuator of gut-associated inflammation, and justify our ongoing dissection of the mechanism-of-action of this novel T cell- epithelial cell axis.