Structural evidence for a germline-encoded T cell receptor–major histocompatibility complex interaction 'codon'

Feng, Dan; Bond, Christopher J.; Ely, Lauren Kate; Maynard, Jennifer A.; García, K. Christopher

doi:10.1038/ni1502

Cited by 206 publications

(286 citation statements)

References 46 publications

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“…This hypothesis is supported by a substantialnumberof crystal structures involving six different Vb8.2 TCRs and one Vb8.1 TCR in complex with mouse I-A molecules. These structures show close convergence of the CDR1b and CDR2b contacts with the I-A a1 chain helix (Reinherz et al 1999;Feng et al 2007;Dai et al 2008;Garcia et al 2009). This Vb8 interaction motif has been seen in structures with different I-A alleles, Va segments, and peptides, and mutation of these TCRb residues reduced or abolished activation by a panel of T cells.…”

Section: Structural Insights Into the Mechanism Of Mhc Restrictionmentioning

confidence: 99%

“…In a series of biochemical studies that included a broad representation of receptor complexes, a set of common features was identified Garrity et al 2005;Feng et al 2006;Feng et al 2007). First, in every case investigated, the association required both aspartic acid residues; alanine substitution of only one in the pair invariably resulted in dramatic assembly defects.…”

Section: Conservation Of Membrane-based Receptor Complex Assemblymentioning

confidence: 99%

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Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Wucherpfennig¹,

Gagnon²,

Call³

et al. 2010

Cold Spring Harbor Perspectives in Biology

148

108

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The T-cell receptor (TCR)-CD3 complex serves as a central paradigm for general principles of receptor assembly, ligand recognition, and signaling in the immune system. There is no other receptor system that matches the diversity of both receptor and ligand components. The recent expansion of the immunological structural database is beginning to identify key principles of MHC and peptide recognition. The multicomponent assembly of the TCR complex illustrates general principles used by many receptors in the immune system, which rely on basic and acidic transmembrane residues to guide assembly. The intrinsic binding of the cytoplasmic domains of the CD31 and z chains to the inner leaflet of the plasma membrane represents a novel mechanism for control of receptor activation: Insertion of critical CD31 tyrosines into the hydrophobic membrane core prevents their phosphorylation before receptor engagement. LIGAND BINDING BY THE EXTRACELLULAR DOMAINS OF T-CELL RECEPTORS: STRUCTURAL BASIS OF ab AND gd TCR BINDING TO A DIVERSE GROUP OF LIGANDST he structures of many T-cellreceptors (TCRs) in their ligand-bound state have now been determined, allowing some of the general rules of antigen recognition to be distilled. Though the best studied interaction is the binding of abTCR with peptide-MHC complexes, it is highly instructive to compare the prototypical binding to peptide-MHC with the recognition of lipid antigen-CD1 complexes and engagement of nonclassical MHC class I molecules by gdTCRs. These comparisons show that the recognition strategies for these

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Section: Structural Insights Into the Mechanism Of Mhc Restrictionmentioning

confidence: 99%

Section: Conservation Of Membrane-based Receptor Complex Assemblymentioning

confidence: 99%

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Wucherpfennig¹,

Gagnon²,

Call³

et al. 2010

Cold Spring Harbor Perspectives in Biology

148

108

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“…One open and interesting controversy is whether it is a germ-line-encoded structure of all TCRs that predisposes the diagonal MHC binding or whether it is a result of positive and negative selection (14). Very recently, structural evidence has suggested that TCRs possess germ-line-encoded structures in their variable regions that recognize MHC molecules independent of the bound peptide (15). These germ-line-encoded TCR-MHC interactions would allow a fast screening of many different pMHCs presented on the target cell by a TCR (16) and might be reflected by the first fast association of the TCR CMV with MHC, as observed by Gakamsky et al Systematic mutations of the TCR and pMHC combined with structural and kinetic measurements could resolve this issue.…”

mentioning

confidence: 99%

The TCR binding site does move

Schamel¹,

Reth²

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent functional data revealed the important role of Y at position 48 of the hTRBV chain in T-cell positive selection, through contacts with the a domains of both class I and class II MHC molecules [17,34]. Strikingly, the BV5 genes (highly expressed both in humans and humanized mice) present this Y at position 48.…”

Section: Discussionmentioning

confidence: 99%

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Pham

Manuel²,

Petit

et al. 2011

Eur J Immunol

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In humanized mice, the T-cell repertoire is derived from genetically identical human progenitors in distinct animals. Thus, careful comparison of the T-cell repertoires of humanized mice with those of humans may reveal the contribution of genetic determinism on T-cell repertoire formation. Here, we performed a comprehensive assessment of the distribution of V-J combinations of the human b chain of the T-cell receptor (hTRBV) in NOD.SCID.cc À/À (NSG) humanized mice. We observed that numerous V-J combinations were equally distributed in the thymus and in the periphery of humanized mice compared with human references. A global analysis of the data, comparing repertoire perturbation indices in humanized NSG mice and unrelated human PBMCs, reveals that 50% of the hTRBV families significantly overlapped. Using multivariate ranking and bootstrap analyses, we found that 18% of all possible V-J combinations contributed close to 50% of the expressed diversity, with significant over-representation of BV5-J1.111.2 and BV6-J1.111.2 rearrangements. Finally, comparison of CD3 À and CD3 1 thymocyte repertoires indicated that the observed V-J combination overlap was already present before TCR-MHC selection in the thymus. Altogether, our results show that half of the T-cell repertoire combinatorial diversity in humans is genetically determined.Key words: Humanized mice . ISEApeaks . Multivariate score . T-cell repertoire . V-J rearrangements Supporting Information available online Introduction T-cell repertoire diversity is based upon tightly ordered genetic rearrangements of the T-cell receptor V, D and J genes. The available numbers of these genes in the genome constitutes a first level of diversity: to date, 33 and 65 genes encoding variable elements of the human T-cell receptor b chain (hTRBV) from 30 hTRBV families have been characterized in mice and humans respectively (according to the ImMunoGeneTics (IMGT) database (http://www.imgt.org)). An additional level of diversity comes from the association of single V, (D) and J elements together. The major determinant of repertoire diversity is then random addition of nucleotides at the junction of these V(D)J gene segments, constituting the CDR3 of the TCR. Finally, a fourth level of complexity originates from the association of the rearranged a and b chains of the TCR. In theory, these sequential processes occurring during T-cell differentiation in the thymus could Eur. J. Immunol. 2012. 42: 760-770 760 generate up to 10 15 different TCRs, a number far in excess of the number of T-cells in the body. The 'real' size of the repertoire is probably much lower though, with recent estimations of unique TCR b chains ranging from 10 6 to 4.10 6 in humans [1,2]. Mice reconstituted with a human immune system generated from hematopoietic precursors represent a new animal model for human immunology studies. The extent of the human T-cell repertoire diversity generated in mice may represent an important functional indicator [3], useful for immunological studies in the models. However, a...

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Structural evidence for a germline-encoded T cell receptor–major histocompatibility complex interaction 'codon'

Cited by 206 publications

References 46 publications

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

The TCR binding site does move

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

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