IFN-γ reverses the stop signal allowing migration of antigen-specific T cells into inflammatory sites

In humans the majority of endothelial cells (EC) constitutively express MHC class 11 Ags. We know that in vitro ECs can activate CD45RO(+) 137-independent CD4(+) T cells to proliferate and produce IL-2. The in vivo correlate of this T cell response is not known, and here we have explored whether endothelial expression of MHC class 11 Ags affects the transendothelial migration of alloreactive CD4(+) CD45RO(+) 137-independent T cells. Alloreactive CD4(+) T cell clones and lines were generated against HLA-DR11, DR13, DR4, and DR1 MHC Ags, and their rates of migration across untreated EC line Eahy.926 (MHC class 11 negative) or Eahy.926 transfected with CIITA (EahyCIITA) to express DR11 and DR13 were investigated. The migrations of EahyCIITA-specific T cell clones and lines were retarded in a DR-specific manner, and retardation was reversed in the presence of mAb to DR Ag. When investigating the ability of T cells to proliferate in response to EahyCIITA before and after transmigration, migrated cells were still able to proliferate, but the frequency of EahyCIITA-specific cells was much reduced compared with that of nonmigrated cells. The use of fluorescently labeled T cells revealed that specific cells become trapped within the endothelial monolayer. Pretreatment of EahyCIITA with IFN-gamma restored the ability of DR11- or DR13-specific T cells to transmigrate and proliferate, thus abrogating DR-specific retardation. We conclude that cognate interaction between T cells and endothelial MHC class 11 initiates a stop signal possibly similar to an immunological synapse, but this is overcome in an inflammatory milieu.