: Integrins are cell surface adhesion molecules highly involved in directing site-specific homing of T cells. This proposal will investigate the molecular mechanisms by which T cells acquire and regulate integrin expression, thus promoting tissue-specific targeting. Following T cell activation, the extra-intestinal homing integrin alpha4beta1 and the gut-homing integrin alpha4beta7 are involved in directing the targeted migration of T cells. However, the molecular mechanism by which their expression is regulated is not well understood. As both of these integrins are involved in trafficking of T cells during autoimmune disease, a deeper understanding of their regulation is of great clinical significance. Integrin regulation is especially relevant to the mission of the NIDDK because integrins are involved in the pathogenesis of inflammatory bowel disease. Preliminary data suggests that expression of betal integrin can modulate alpha4beta7 integrin expression and thus alter T cell homing preference. Utilizing a novel mouse model system, the mechanism by which betal integrin expression results in modulation of gut-homing alpha4beta7 expression will be evaluated. The ability of T cells lacking or overexpressing betal integrin to mediate intestinal inflammation will be assessed. Recent data suggests opposing roles for vitamin A and vitamin D metabolites in regulation of T cell targeting through modulation of cell surface adhesion molecules. With this in mind, the specific mechanism by which betal integrin expression is regulated on T cells will be explored through a series of in vitro and in vivo activation studies. Particular attention will be devoted to the role of vitamin D in the regulation of betal integrin expression. Relevance of research to public health: The proposed work will expand upon the understanding of how integrin expression and thus homing of T cells is regulated. By determining the mechanism by which T cells regulate integrin expression, it may become possible to specifically control the trafficking of T cells! This has direct application to the development of T cell-modulating therapeutics and more effective immunization protocols.
| DeNucci, Christopher C; Shimizu, Yoji (2011) ?1 integrin is critical for the maintenance of antigen-specific CD4 T cells in the bone marrow but not long-term immunological memory. J Immunol 186:4019-26 |
| DeNucci, Christopher C; Pagán, Antonio J; Mitchell, Jason S et al. (2010) Control of alpha4beta7 integrin expression and CD4 T cell homing by the beta1 integrin subunit. J Immunol 184:2458-67 |
| Denucci, Christopher C; Mitchell, Jason S; Shimizu, Yoji (2009) Integrin function in T-cell homing to lymphoid and nonlymphoid sites: getting there and staying there. Crit Rev Immunol 29:87-109 |
