Crystal structure of human CD4 complexed with MHC class II, peptide and T cell receptor (100.47)

Abstract

Abstract The recognition of agonist peptide and MHC class II by T cell receptor (TCR) triggers the activation and development of CD4+ T cells. CD4, as the co-receptor, plays an important role in T cell signaling. Wild-type CD4 contacts the non-polymorphic domains of MHC class II with remarkably low affinity. By using an affinity-matured CD4 molecule, we determined the X-ray crystal structure of the ternary complex between the four Ig-like domains of human CD4 (D1-D4) and a TCR bound to HLA-DR4 bearing an agonist peptide (pMHC). The structure precludes direct CD4-TCR contacts, but provides ample room for the placement of CD3 subunits. Importantly, the CD4-pMHC-TCR complex is incompatible with models for TCR triggering involving MHC or CD4 dimerization. On the other hand, it is compatible with a recent model for T cell activation involving TCR dimerization via the Cα domain. The structure also suggests that non-canonical TCR docking modes, such as those observed in certain autoimmune TCR-pMHC complexes, may affect the association with CD4 and thereby alter T cell triggering. Collectively, our results provide a picture of the CD4-pMHC-TCR signaling complex that will be useful for understanding the initiation events of T cell activation.