Presidential Address to The American Association of Immunologists

Marrack, Philippa; Bender, Jeremy; Jordan, Michael; Rees, William; Rosenstein, Jennifer; Schaefer, Brian C.; Kappler, John W.

doi:10.4049/jimmunol.167.2.617

Cited by 22 publications

(19 citation statements)

References 50 publications

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“…It was recently predicted that the naturally selected mature T cell repertoire contains remnants of conserved interactions with MHC residues and that these residues vary from one TCR/MHC pair to another (39). Evidence in favor of this prediction may be obtained by comparison of the data presented in this report on TCR/HLA-A2 with data on recognition of TCR/H-2K b (40).…”

Section: Discussionmentioning

confidence: 63%

MHC Allele-Specific Molecular Features Determine Peptide/HLA-A2 Conformations That Are Recognized by HLA-A2-Restricted T Cell Receptors

Wang

Turner

Baker

et al. 2002

The Journal of Immunology

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The structures of αβ TCRs bound to complexes of class I MHC molecules and peptide show that the TCRs make multiple contacts with the α1 and α2 helixes of the MHC. Previously we have shown that the A6 TCR in complex with the HLA-A2/Tax peptide has 15 contact sites on HLA-A2. Single amino acid mutagenesis of these contact sites demonstrated that mutation of only three amino acids clustered on the α1 helix (R65, K66, A69) disrupted recognition by the A6 TCR. In the present study we have asked whether TCRs that recognize four other peptides presented by HLA-A2 interact with the MHC in identical, similar, or different patterns as the A6 TCR. Mutants K66A and Q155A had the highest frequency of negative effects on lysis. A subset of peptide-specific CTL also selectively recognized mutants K66A or Q155A in the absence of exogenous cognate peptides, indicating that these mutations affected the presentation of endogenous peptide/HLA-A2 complexes. These findings suggest that most HLA-A2-restricted TCRs recognize surfaces on the HLA-A2/peptide complex that are dependent upon the side chains of K66 and Q155 in the central portion of the peptide binding groove. Crystallographic structures of several peptide/HLA-A2 structures have shown that the side chains of these critical amino acids that make contact with the A6 TCR also contact the bound peptide. Collectively, our results indicate that the generalized effects of changes at these critical amino acids are probably due to the fact that they can be directly contacted by TCRs as well as influence the binding and presentation of the bound peptides.

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Section: Discussionmentioning

confidence: 63%

MHC Allele-Specific Molecular Features Determine Peptide/HLA-A2 Conformations That Are Recognized by HLA-A2-Restricted T Cell Receptors

Wang

Turner

Baker

et al. 2002

The Journal of Immunology

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“…Our first objective was to obtain single-molecule level fluorescence detection of T cell surface receptors. Three different murine T cell hybridomas were used in the present study: the V ␤ 8 ϩ DO11.10 T cell hybridoma (24); a second V ␤ 8 ϩ hybridoma, YAe5B3K (25); and the V ␤ 8 Ϫ hybridoma, KMAC92.6 (26). The two V ␤ 8 ϩ hybridomas were used to minimize hybridoma-specific artifacts, whereas the third was used as a labeling control.…”

Section: Resultsmentioning

confidence: 99%

Single-molecule level analysis of the subunit composition of the T cell receptor on live T cells

James

White

Clarke

et al. 2007

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

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The T cell receptor (TCR) expressed on most T cells is a protein complex consisting of TCR␣␤ heterodimers that bind antigen and cluster of differentiation (CD) 3␦, ␥, and dimers that initiate signaling. A long-standing controversy concerns whether there is one, or more than one, ␣␤ heterodimer per complex. We used a form of single-molecule spectroscopy to investigate this question on live T cell hybridomas. The method relies on detecting coincident fluorescence from single molecules labeled with two different fluorophores, as the molecules diffuse through a confocal volume. The fraction of events that are coincident above the statistical background is defined as the ''association quotient,'' Q. In control experiments, Q was significantly higher for cells incubated with wheat germ agglutinin dual-labeled with Alexa488 and Alexa647 than for cells incubated with singly labeled wheat germ agglutinin. Similarly, cells expressing the homodimer, CD28, gave larger values of Q than cells expressing the monomer, CD86, when incubated with mixtures of Alexa488-and Alexa647-labeled antibody Fab fragments. T cell hybridomas incubated with mixtures of anti-TCR␤ Fab fragments labeled with each fluorophore gave a Q value indistinguishable from the Q value for CD86, indicating that the dominant form of the TCR comprises single ␣␤ heterodimers. The values of Q obtained for CD86 and the TCR were low but nonzero, suggesting that there is transient or nonrandom confinement, or diffuse clustering of molecules at the T cell surface. This general method for analyzing the subunit composition of protein complexes could be extended to other cell surface or intracellular complexes, and other living cells.cell membrane ͉ organization ͉ protein ͉ spectroscopy ͉ TCR/CD3 complex T he cell surface, which has a central role in determining cellular function and fate, presents a particular challenge for the in situ analysis of protein organization because of the relatively low levels of expression of many of the molecules present there. Whereas the overall compositional complexity of the best characterized mammalian cell surface, that is, that of the T cell, is now largely known (1), the organizational properties of some of its most important constituents are poorly characterized. The outstanding example is the T cell receptor (TCR), which initiates T cell activation by binding antigenic peptides complexed with MHC molecules expressed on antigen-presenting cells. The TCR consists of the clonotypic, antigen-binding, disulfide-linked TCR ␣ and ␤ (or ␥ and ␦) chains, which are noncovalently associated with the signaling subunits, CD3␥, ␦, , and . Precisely how these elements are assembled beyond the formation of TCR␣␤ (or ␥␦), ␦, and ␥ heterodimers and homodimers (2) is not known. It has variously been proposed that the TCR is monovalent (i.e., consists of a single ␣␤ (or ␥␦) heterodimer; see refs. 3 and 4), invariably multivalent (5), or a mixture of the two (6). When it is finally understood in detail, the structure of the TCR is likely to place imp...

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“…Two types of histocompatibility molecules, class I and II, are expressed in nucleated cells or antigen-presenting cells, respectively. The class I and class II MHC genes encode cell surface heterodimers; they play an important role in antigen presentation, tolerance and self/non-self recognition [1][2][3]. The MHC class I molecules form a stable tri-molecular complex composed of an MHC-encoded heavy chain, beta-2 microglobulin and small peptides.…”

Section: Genetic and Functional Variation Of Major Histocompatibilitymentioning

confidence: 99%

“…In live cells, the peptides presented in these complexes derive from intracellular proteins; this complex is the ligand of the antigen receptor of cytotoxic T-lymphocytes. In these molecules, some sub-structures, called peptide-binding specificity pockets, accommodate the side chains of the bound peptides [3][4][5][6][7]. The MHC class II molecules are also tri-molecular complexes, composed of a peptide and two subunits (alpha and beta) that are encoded in the MHC; in the case of the class II molecules, the peptides presented derive from extracellular proteins that are endocytosed in the antigen-presenting cells.…”

Section: Genetic and Functional Variation Of Major Histocompatibilitymentioning

confidence: 99%

Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations

Viña

Hollenbach²,

Lyke

et al. 2012

Phil. Trans. R. Soc. B

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The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses.

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Presidential Address to The American Association of Immunologists

Cited by 22 publications

References 50 publications

MHC Allele-Specific Molecular Features Determine Peptide/HLA-A2 Conformations That Are Recognized by HLA-A2-Restricted T Cell Receptors

MHC Allele-Specific Molecular Features Determine Peptide/HLA-A2 Conformations That Are Recognized by HLA-A2-Restricted T Cell Receptors

Single-molecule level analysis of the subunit composition of the T cell receptor on live T cells

Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations

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