T Cell Antigen Receptor Recognition of Antigen-Presenting Molecules

Abstract

The Major Histocompatibility Complex (MHC) locus encodes classical MHC class I and MHC class II molecules and nonclassical MHC-I molecules. The architecture of these molecules is ideally suited to capture and present an array of peptide antigens (Ags). In addition, the CD1 family members and MR1 are MHC class I-like molecules that bind lipid-based Ags and vitamin B precursors, respectively. These Ag-bound molecules are subsequently recognized by T cell antigen receptors (TCRs) expressed on the surface of T lymphocytes. Structural and associated functional studies have been highly informative in providing insight into these interactions, which are crucial to immunity, and how they can lead to aberrant T cell reactivity. Investigators have determined over thirty unique TCR-peptide-MHC-I complex structures and twenty unique TCR-peptide-MHC-II complex structures. These investigations have shown a broad consensus in docking geometry and provided insight into MHC restriction. Structural studies on TCR-mediated recognition of lipid and metabolite Ags have been mostly confined to TCRs from innate-like natural killer T cells and mucosal-associated invariant T cells, respectively. These studies revealed clear differences between TCR-lipid-CD1, TCR-metabolite-MR1, and TCR-peptide-MHC recognition. Accordingly, TCRs show remarkable structural and biological versatility in engaging different classes of Ag that are presented by polymorphic and monomorphic Ag-presenting molecules of the immune system.

Identification of the Docking Site for CD3 on the T Cell Receptor β Chain by Solution NMR

“…Indeed, recent studies in several systems have demonstrated that ligand binding can alter protein flexibility at distant sites, resulting in long range transmission of biological signals, even in the absence of crystallographically observed structural changes (47)(48)(49)(50). This process, known as dynamic allostery, is of special interest in cases such as the TCR, where x-ray crystallographic studies of multiple TCRs in free form and bound to pMHC have so far failed to identify clear and consistent conformational changes in the TCR C␣ or C␤ domains that could be unambiguously attributed to antigen binding (4,8,10). Future studies will examine the possibility that MBP-HLA-DR4 ligation by MS2-3C8 induces allosteric changes in TCR dynamics that are transmitted to the CD3 signaling apparatus.…”

Determinants of Gliadin-Specific T Cell Selection in Celiac Disease

“…Affinities of this magnitude are typically associated with TCRs that recognize nonself/microbial epitopes (25,26). We previously observed how HLA-DQ8-glia-a1 recognition by a TRAV26-2/TRBV9 TCR and HLA-DQ2-glia-a2 recognition by three TRAV26-1/TRBV7-2 TCRs depended on a CDR3-encoded Arg (9,10).…”

Mechanosensing drives acuity of αβ T-cell recognition

“…T he T-cell receptor (TCR) expressed on T lymphocytes of the adaptive immune system is a stout and squat (12-nm wide × 8-nm tall) multisubunit surface complex with a ligand binding moiety that is an αβ disulfide-linked heterodimer buttressed by the associated invariant CD3 subunits (1)(2)(3). The αβ chains are each encoded by V and J gene segments and in the case of the β, a D segment as well (4).…”