Structure of the complex between human T-cell receptor, viral peptide and HLA-A2

Garboczi, David N.; Ghosh, Partho; Utz, Ursula; Fan, Qing; Biddison, William E.; Wiley, Don C.

doi:10.1038/384134a0

Cited by 1,321 publications

(1,157 citation statements)

References 46 publications

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“…In order to raise antibodies against the human invariant Va24-Ja18 TCR, a cyclic peptide representing the predicted CDR3 loop of the invariant TCRa sequence [CH2CO-CVVSDRGSTLGRLAD-C (thioether linkage to CH 2 )-G-COOH] was modeled using previous TCR crystal structures as templates [48,49]. The peptide was cyclized in situ using a thioether linkage, followed by deprotection of the N-terminal Cys residue and release from the resin for purification (SynPep, Dublin, CA).…”

Section: Isolation Of Invariant Tcr Cdr3 Loop-specific Antibodiesmentioning

confidence: 99%

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Exley¹,

Hou²,

Shaulov³

et al. 2008

Eur J Immunol

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A significant fraction of CD1d-restricted T cells express an invariant T cell receptor (TCR) a-chain. These highly conserved invariant NKT (iNKT) populations are important regulators of a wide spectrum of immune responses. The ability to directly identify and manipulate iNKT cells is essential to understanding their function and to exploit their therapeutic potential. To this end, we sought monoclonal and polyclonal antibodies specific for iNKT cells by immunizing CD1d KO mice, which lack iNKT cells, with a cyclic peptide modeled after the TCRa CDR3 loop. One mAb (6B11) was specific for cloned and primary human but not rodent iNKT cells and the human invariant TCRa, as shown by transfection and reactivity with human invariant TCRa transgenic T cells ex vivo and in situ. 6B11 was utilized to identify, purify, and expand iNKT cells from an otherwise minor component of human peripheral blood lymphocytes and to specifically identify human iNKT cells in tissue. Thus, we report a novel and general strategy for the generation of mAb specific for the CDR3 loop encoded by the TCR of interest. Specifically, an anti-Va24Ja18 CDR3 loop clonotypic TCR mAb is available for the enumeration and therapeutic manipulation of human and non-human primate iNKT populations.Key words: Anti-TCR Á Clonotypic Á Cyclic peptide Á IL-4 Á Invariant NKT Introduction Natural killer T (NKT) cells expressing surface markers found on NK cells (e.g. CD161, CD56, CD94 and/or KIR) comprise up to 20% of human peripheral blood lymphocytes (PBL) [1], whilst only *0.05% of PBL are CD1d restricted [2][3][4]. A major proportion of such PBL CD1d-reactive T cells are invariant NKT (iNKT) cells in that they express an invariant TCR a-chain, Va24Ja18 in humans and Va24Ja18 in mice [3,5,6]. Both human and murine iNKT cells can be activated in a CD1d-dependent fashion by the synthetic glycolipid a-galactosylceramide (a-GalCer) and self-or pathogen-derived glycolipid molecules [7][8][9]. Activation of iNKT cells leads to rapid production of large amounts of numerous cytokines and consequent stimulation of Mark A. Exley et al. Eur. J. Immunol. 2008. 38: 1756-1766 [3,[10][11][12][13][14], perhaps most significantly by regulating dendritic cell (DC) function [10,15]. The frequency and functional activity of iNKT cells have been shown to be important determinants for the progression of autoimmune disorders, tumors, and viral infections [10,[16][17][18]. In humans, a reduction in the number of circulating iNKT cells is accompanied by a striking Th1 polarization in certain autoimmune diseases such as type 1 diabetes, systemic sclerosis and rheumatoid arthritis [18][19][20][21]. Cancer patients have decreased numbers of iNKT cells in their blood and impaired in vitro proliferative potential, reversible with IL-2 [22][23][24]. As well as the reduced numbers of these cells found in many cancer patients, there is a striking reversal of cytokine polarization relative to that found in diabetes, which may reflect a reduction in iNKT anti-tumor activity during progression [...

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Section: Isolation Of Invariant Tcr Cdr3 Loop-specific Antibodiesmentioning

confidence: 99%

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Exley¹,

Hou²,

Shaulov³

et al. 2008

Eur J Immunol

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“…A few years later, Wiley and colleagues [53] elucidated the structure of the complex between TCR, viral peptide, and MHC. Finally, immunologists were provided with a crystal-clear picture of T cell:altered-self interaction.…”

Section: The Enlightenmentmentioning

confidence: 99%

A brief history of CD8 T cells

et al. 2007

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“…It is probably not only by chance that within a few weeks of the news of this year's Nobel Prize for specificity of the cell-mediated immune response, the first studies appeared in Science and Nature, revealing the X-ray structure of the complete complex of the T-cell receptor-MHC class I plus the bound peptide by I. A. Wilson and by D. Wiley and their coworkers [69,70]. What is less clear, in 1996, is which part of the TCR, and whether corresponding parts of the TCR always recognized the peptide and the MHC molecule in the same general position [71,72] ( Fig.…”

Section: Further Analysismentioning

confidence: 99%

Cellular Immune Recognition and the Biological Role of Major Transplantation Antigens

Zinkernagel

1997

Scand J Immunol

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Structure of the complex between human T-cell receptor, viral peptide and HLA-A2

Cited by 1,321 publications

References 46 publications

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

A brief history of CD8 T cells

Cellular Immune Recognition and the Biological Role of Major Transplantation Antigens

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