MAdCAM signaling through integrin α4β7 modulates surface expression of CCR5 and markers of CD4+ T cell activation.

Integrin α 4 β 7 mediates homing of lymphocytes, including CD4+ T cells, to gut-associated lymphoid tissue(GALT) through an interaction with Mucosal AddressinCell Adhesion Molecule (MAdCAM), expressed on gut endothelial venules. MAdCAM facilitates rolling adhesion of CD4 + T lymphocytes along the gut endothelium prior to extravasation. Previous work also indicates that MAdCAM interactions with α 4 β 7 provide a co-stimulatory signal to T cells. α 4 β 7 + /CD4 + T cells are a preferred target of HIV during the acute phase of infection. We hypothesized that signaling through α 4 β 7 via MAdCAM renders cells susceptible to HIV infection and replication. In this study we characterized the response of α 4 β 7 + /CD4 + T cells to costimulation via MAdCAM in order to better understand whether the induced phenotype would support an enhanced degree of viral replication. We found that CD4 + T cells upregulated CCR5, an HIV coreceptor, in response to MAdCAM costimulation. We also observed the rapid induction of CD69, a known marker of activation. This induction was restricted to α 4 β 7 + cells, including both the CD45RO + α 4 β 7 + memory subset and CD45RO neg /α 4 β 7 + naive cell subset. We also observed decreased surface expression of two MAdCAM ligands; integrin β 7 + was down-regulated within four hours post MAdCAM costimulation and L-selectinwas shed with similar kinetics. This shedding occurred primarily in the CD45RO neg subset. Overall these results indicate that MAdCAM-mediated costimulation through α 4 β 7 activates CD4 + T cells in a unique manner that is likely conducive to viral replication. Of note we found that CCR5, the principal HIV coreceptor, was upregulated. Interestingly, the surface expression of two MAdCAM ligands, L-selectinand α 4 β 7 , were both reduced.