Conserved and Heterogeneous Lipid Antigen Specificities of CD1d-Restricted NKT Cell Receptors

Brigl, Manfred; Elzen, Peter van den; Chen, Xiuxu; Meyers, Jennifer Hartt; Wu, Dawei; Wong, Chi‐Huey; Reddington, Faye; Illarianov, Petr A.; Besra, Gurdyal S.; Brenner, Michael B.; Gumperz, Jenny E.

doi:10.4049/jimmunol.176.6.3625

Cited by 91 publications

(127 citation statements)

References 39 publications

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“…anti-Va24-PE antibody) [28,29]. Concurrent incubation with anti-Va24 antibody has been used to block tetramer binding to iNKT and thus identify non-invariant CD1d-restricted populations [28,29]. Previous estimates of the relative contribution of the iNKT subset to the total population of CD1d-restricted T cells has been limited by the lack of a comprehensive set of self antigens, and the use of various strains of mice with iNKT-related gene deletions [35].…”

Section: Discussionmentioning

confidence: 99%

“…Fig. 3C) [28,29]. The biological function of such variant CD1d-restricted T cells is poorly understood.…”

mentioning

confidence: 99%

“…The biological function of such variant CD1d-restricted T cells is poorly understood. There is good evidence that variant populations are selected by and recognizes self antigens processed from different cellular compartments [29,30]. Even co-expression of Va24 and Vb11 does not completely overlap with CD1d tetramer reactivity in humans and can be complicated by competition between CD1d tetramers and anti-TCR mAb or their often bulky chromophores (e.g.…”

mentioning

confidence: 99%

“…Even co-expression of Va24 and Vb11 does not completely overlap with CD1d tetramer reactivity in humans and can be complicated by competition between CD1d tetramers and anti-TCR mAb or their often bulky chromophores (e.g. anti-Va24-PE antibody) [28,29]. Concurrent incubation with anti-Va24 antibody has been used to block tetramer binding to iNKT and thus identify non-invariant CD1d-restricted populations [28,29].…”

mentioning

confidence: 99%

“…A number of groups have reported selective identification of CD1d-restricted T cells ex vivo with CD1d multimers specifically loaded with a-GalCer [4,27]. Whilst this approach has been powerful for the enumeration of a-GalCer-reactive T cells, limitations include the possibility of identifying CD1d-reactive cells that are noninvariant and whose functionality is unclear, as well as missing iNKT cells with sufficiently divergent TCR that do not react with a-GalCer [28][29][30]. Furthermore, functional application of tetramer reagents is complex and they are generally not useful in histology [4].…”

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confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…Fig. 3C) [28,29]. The biological function of such variant CD1d-restricted T cells is poorly understood.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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Synovial fibroblasts self‐direct multicellular lining architecture and synthetic function in three‐dimensional organ culture

Kiener¹,

Watts²,

Cui³

et al. 2010

Arthritis & Rheumatism

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103

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The Roles of 3′ and 4′ Hydroxy Groups in α‐Galactosylceramide Stimulation of Invariant Natural Killer T Cells

Xia

Zhang

et al. 2009

ChemMedChem

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The marine-derived α-galactosylceramide is an exogenous ligand for natural killer T cells and leads to the secretion of both T help 1 (Th1) and Th2 cytokines. The relationship between the sugar moiety structure and invariant natural killer T (iNKT) cell stimulation ability has not been fully understood. With the series α-galactosylceramide analogues varied on C3′ and C4′ position, subjected to a murine system, we discovered that the 3′ hydroxyl is very crucial in maintaining the molecule’s immunogenicity. Any modification on this position will lead to the losing of activity. We also found that the C4′ position is not so sensitive and can tolerate some small modifications on it. Moreover, the C4′ substituted analogues induced biased Th2 cytokines release was observed.

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Conserved and Heterogeneous Lipid Antigen Specificities of CD1d-Restricted NKT Cell Receptors

Cited by 91 publications

References 39 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

Synovial fibroblasts self‐direct multicellular lining architecture and synthetic function in three‐dimensional organ culture

The Roles of 3′ and 4′ Hydroxy Groups in α‐Galactosylceramide Stimulation of Invariant Natural Killer T Cells

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