T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand

Abstract

The binding of a T-cell antigen receptor (TCR) to peptide antigen presented by major histocompatibility antigens (pMHC) on antigen-presenting cells (APCs) is a central event in adaptive immune responses. The mechanism by which TCR-pMHC ligation initiates signalling, a process termed TCR triggering, remains controversial. It has been proposed that TCR triggering is promoted by segregation at the T cell-APC interface of cell-surface molecules with small ectodomains (such as TCR-pMHC and accessory receptors) from molecules with large ectodomains (such as the receptor protein tyrosine phosphatases CD45 and CD148). Here we show that increasing the dimensions of the TCR-pMHC interaction by elongating the pMHC ectodomain greatly reduces TCR triggering without affecting TCR-pMHC ligation. A similar dependence on receptor-ligand complex dimensions was observed with artificial TCR-ligand systems that span the same dimensions as the TCR-pMHC complex. Interfaces between T cells and APCs expressing elongated pMHC showed an increased intermembrane separation distance and less depletion of CD45. These results show the importance of the small size of the TCR-pMHC complex and support a role for size-based segregation of cell-surface molecules in TCR triggering.

Human Major Histocompatibility Complex (MHC) Class I Molecules with Disulfide Traps Secure Disease-related Antigenic Peptides and Exclude Competitor Peptides

“…More specifically, an SCT based on human HLA-E, a non-classical or MHC class Ib molecule loaded with an MHC class Ia signal peptide was expressed on porcine cells and shown to inhibit NK cells killing as mediated by the CD94/ NKG2A inhibitory receptor. In another study, SCTs were used to demonstrate the importance of size-based molecular segregation for immune synapse formation (54). Along these same lines, a future application of SCTs should be to definitively test the importance of non-cognate co-receptor interactions in immune synapses (55).…”

The human CD94 gene encodes multiple, expressible transcripts including a new partner of NKG2A/B

“…In this case, it was shown that Tcell receptor signaling but not ligation is critically dependent on the overall size of the interacting ligands and that size based segregation of TCR-MHC complexes is important for maximal signaling. 34 It was argued that receptor-ligand dimensions are likely to be very important for receptor-ligand systems that depend on tyrosine phosphorylation of their cytoplasmic tail by tyrosine kinases, 35 as is the case for the CD94/NKG2A, -B receptors after interaction with their ligand HLA-E.…”

Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

“…Based on the concept that the cell surface receptors are spatially distributed according to their dimension (Choudhuri et al, 2005), we elongated the PD-1 ectodomain by the insertion of the Ig domains of the unrelated Ig super family molecules human (h) CD22 or hCD4 to make the fusion protein distinct in height from the TCR (Fig. 7 A).…”