CTLA-4 differentially regulates the immunological synapse in CD4 T cell subsets

Primary murine Th1 and Th2 cells differ in the organization of the immunological synapse, with Thl cells, but not Th2 cells, clustering signaling molecules at the T cell/B cell synapse site. We sought to determine whether differential costimulatory signals could account for the differences observed. We found that Th2 cells express higher levels of CTLA-4 than Thl cells, and demonstrated that Th2 cells lacking CTLA-4 are now able to cluster the TCR with the same frequency as Thl cells. Furthermore, reconstitution of CTLA-4 into CTLA-4-deficient Th2 cells, or into Thl cells, inhibits the clustering of the TCR. We have also shown that Th2 cells, but not Thl cells, show variations in the organization of the immunological synapse depending on levels of expression of CD80/CD86 on the APC. These studies demonstrate a unique role for CTLA-4 as a critical regulator of Th2 cells and the immunological synapse.