For example, CD8αβ did not contact the α2 and β2m domains of H-2Dd, which reduced the buried surface area of this complex compared with murine pMHCI–CD8αα. Accumulated structural evidence of TCR–pMHC interactions

has shown that the TCR binds with a conserved general topology, with the TCR α-chain positioned over the N-terminus of the peptide and the TCR β-chain over the C-terminus.[30] It has been postulated that this binding mode is essential to allow co-receptor binding to the same pMHC as the TCR at the cell surface (Fig. 1).[31] Hence, the CD8 co-receptor (and CD4 co-receptor) may have a role in governing the conserved binding mode of the TCR to allow the formation of a functional signalling complex at the T-cell surface.[32] Indeed, Kuhns and Davis[33] have shown that the ectodomains of CD3εδ and CD3εγ, that constitute an important Ivacaftor cell line selleck part of the TCR signalling complex, associate with the Cα DE and

Cβ CC’ loops, respectively, within the constant domain of the TCR (Fig. 3a). In this study, mutation of these conserved loops disrupted the formation of the TCR–CD3 signalling domain and subsequent T-cell activation. So it seems that these CD3 subunits, that contain intracellular tyrosine kinase activation motifs and play an important role in providing T-cell activation signals, form specific interactions with the TCR, fixing their position at the cell surface with respect to the TCR. Yin et al.[32] showed that the structure of the tripartite TCR–pMHCII–CD4 complex is compatible with this notion. Assuming that the TCR and co-receptor co-engage the same pMHC at the cell surface, the fixed polarity of the TCR–pMHC interaction beta-catenin inhibitor could orientate the co-receptor in such a way as to

allow the CD3 molecules to lie between the TCR and co-receptor (Fig. 3a,b). This would position the intracellular signalling domains of CD3 and the co-receptor in close proximity to enable cross-signalling during antigen engagement. If the TCR bound in the reverse polarity, with the TCR β-chain over the peptide N-terminus and the TCR α-chain over the C-terminus, the CD3 complex would lie distal from the co-receptor, and this could presumably reduce the efficiency of the T-cell activation signal between the co-receptor and the CD3 complex (Fig. 3c,d). Adding further support to the idea that the T-cell co-receptors can influence the nature of TCR antigen recognition, Van Laethem et al.[34] have shown that the CD4 and CD8 co-receptors impose MHC-restriction on T cells by preventing Lck availability during TCR interactions with non-MHC antigens. Indeed, in the absence of the co-receptors T cells develop with antibody-like specificities that can respond to other cell surface molecules, such as CD155.