Structural understanding of T cell receptor triggering

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Abstract

The T cell receptor (TCR) is one of the most complicated receptors in mammalian cells, and its triggering mechanism remains mysterious. As an octamer complex, TCR comprises an antigen-binding subunit (TCRαβ) and three CD3 signaling subunits (CD3ζζ, CD3δε, and CD3γε). Engagement of TCRαβ with an antigen peptide presented on the MHC leads to tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in CD3 cytoplasmic domains (CDs), thus translating extracellular binding kinetics to intracellular signaling events. Whether conformational change plays an important role in the transmembrane signal transduction of TCR is under debate. Attracted by the complexity and functional importance of TCR, many groups have been studying TCR structure and triggering for decades using diverse biochemical and biophysical tools. Here, we synthesize these structural studies and discuss the relevance of the conformational change model in TCR triggering.

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How TCRs bind MHCs, peptides, and coreceptors.

Markus Rudolph, Robyn L. Stanfield, Ian A Wilson (2006)

Since the first crystal structure determinations of alphabeta T cell receptors (TCRs) bound to class I MHC-peptide (pMHC) antigens in 1996, a sizable database of 24 class I and class II TCR/pMHC complexes has been accumulated that now defines a substantial degree of structural variability in TCR/pMHC recognition. Recent determination of free and bound gammadelta TCR structures has enabled comparisons of the modes of antigen recognition by alphabeta and gammadelta T cells and antibodies. Crystal structures of TCR accessory (CD4, CD8) and coreceptor molecules (CD3epsilondelta, CD3epsilongamma) have further advanced our structural understanding of most of the components that constitute the TCR signaling complex. Despite all these efforts, the structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes. Notwithstanding, the impressive array of self, foreign (microbial), and autoimmune TCR complexes have uncovered the diverse ways in which antigens can be specifically recognized by TCRs.

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Therapeutic T cell engineering

Michel Sadelain, Isabelle Rivière, Stanley Riddell (2017)

Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered

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T cell antigen receptor recognition of antigen-presenting molecules.

Jamie Rossjohn, Stéphanie Le Gras, John J. Miles … (2015)

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.