The ups and downs of T cells The role of costimulatory molecules in the modulation of T cell responses

Sammanfattning: T cell activation requires the combination of antigen in the context of MHC and costimulatory molecules to induce a functional immune response. For our studies, we primarily utilized superantigens (SAg) that bind MHC class II molecules as first signal. Mutations in the SAg MHC class II a-chain binding site reduced the number of responding T cells expressing particular TCR Vb chains, whereas mutation in the SAg MHC class b-chain binding site reduced mitogenicity rather than not TCR Vb specificity. SAg-mediated activation of T cells is equally dependent on costimulatory molecules as activation with antigen fragments in the context of MHC. The costimulatory ligand CD86 together with SAg mediated activation, induced lower transcriptional activity of AP-1 and NF-kB transcription factors, whereas the transcriptional activity of these elements are substantially enhanced in the presence of SAg and CD80. We have suggested that CD86 is important in initial autocrine IL-2 production, whereas CD80 is more important for a paracrine IL-2 production for prolongation of the immune response. The T cell receptor CD152 (CTLA-4) is critical for downregulation of T cell activation. We showed that CD152 induced termination is due to strongly suppressed levels of NF-kB and AP-1, as well as to reduced phosphorylation of IkB-k. Inhibition by CD152 co-ligation could be demonstrated only in the presence of co-ligated CD28, which suggests that the main function of CD152 is suppression of the T cell response by modulating the CD28 signalling pathway.