BUTIES · The role of Butyrophilin-like molecule 1 in intestinal epithelial cell-T cell interactions and immune surveillance
FP7 — People (Marie Curie Actions)
- Duration
- 2010-01-05 → 2012-07-04
- EU contribution
- €180,217
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
The butyrophilin-like (Btnl) molecules share similarities with the B7 family of costimulatory molecules for T cells, yet no functions are known. They are encoded in the major-histocompatibility complex (MHC) locus, a region of the genome known to be highly relevant in many diseases. Recently, Professor Hayday's lab identified a novel immunoglobulin-related molecule, Skint1, which appears to be a selection determinant for skin gamma delta T cells. Furthermore, in the absence of Skint1 and normal skin gamma delta T cells, mice develop spontaneous skin inflammation and are susceptible to skin carcinomas. Hence, Skint1 seems to underpin key aspects of skin immune surveillance. Interestingly, Skint1 shares close sequence homology with Btnl1, 4 and 6; moreover, whereas Skint1 is expressed specifically in thymus and skin epithelia, Btnl1, 4 and 6 are expressed specifically by intestinal epithelia. The gut is a site of chronic immune stimulation where the control of tissue inflammation and stress responses is very important. Therefore, the functional relatedness of Skint1 and the Btnl family provoked our hypothesis that Btnl1 and its relatives may be novel regulators of immunosurveillance, by interacting with intraepithelial lymphocytes (IEL) in the gut. Indeed, human Btnl2 is genetically associated with sarcoidosis and ulcerative colitis. To investigate Btnl1, I will use novel anti-Btnl1 antibodies, a Btnl1-Fc fusion protein and Btnl1 knockout mice to define situations in which Btnl1 receptor engagement occurs and the significance of this interaction. I will also attempt to identify the Btnl1 receptor on IEL. Finally, I wish to address the role of Btnl1 in immune surveillance, by examining the interaction of IEL and Btnl1+ cells in a mouse model of epithelial stress. By this, I hope to be able to place Btnl1 in the context of tumour immunology and inflammatory diseases of the gut, by characterising a potential target for clinical manipulation.
Original text from CORDIS.
Participants
- KING'S COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union