An invariant V alpha 24-J alpha Q/V beta 11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells.

Dellabona, Paolo; Padovan, Elisabetta; Casorati, Giulia; Brockhaus, Manfred; Lanzavecchia, Antonio

doi:10.1084/jem.180.3.1171

Cited by 410 publications

(304 citation statements)

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“…Stimulation of healthy donor iNKT cells triggers both secretion of multiple cytokines including IFN-c and CD1d-specific cytotoxic activity, which in the human involves perforin/granzyme granule secretion [2,4]. Thus, iNKT cells are clearly important regulators of a widely disparate set of immune responses, making them attractive targets for therapeutic intervention.Human iNKT cells were originally identified with Va24 and Vb11 mAb [26], but even the combination of these two relatively selective reactivities does not formally define iNKT cells [5]. 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].…”

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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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confidence: 99%

“…Human iNKT cells were originally identified with Va24 and Vb11 mAb [26], but even the combination of these two relatively selective reactivities does not formally define iNKT cells [5]. 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].…”

mentioning

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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“…Natural killer T (NKT) cells are a unique lymphocyte subset, which in humans are characterized by the presence of an invariant T-cell receptor (TCR) Va24 þ Vb11 þ associated with the natural killer (NK) receptor NKR-P1A (Dellabona et al, 1994). Unlike conventional T cells human NKT cells and their murine counterpart, Va14 NKT cells are activated by the glycolipid, a-galactosylceramide (a-GalCer) presented by a nonpolymorphic major histocompatability complex (MHC) class I-like molecule CD1d (Kawano et al, 1999b;Nieda et al, 1999).…”

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Modulation of human Vα24+Vβ11+ NKT cells by age, malignancy and conventional anticancer therapies

Crough

Purdie²,

Okai³

et al. 2004

Br J Cancer

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Immunotherapy strategies aimed at increasing human Va24 þ Vb11 þ natural killer T (NKT) cell numbers are currently a major focus. To provide further information towards the goal of NKT cell-based immunotherapy, we assessed the effects of age, cancer status and prior anticancer treatment on NKT cell numbers and their expansion capacity following a-galactosylceramide (a-GalCer) stimulation. The percentage and absolute number of peripheral blood NKT cells was assessed in 40 healthy donors and 109 solid cancer patientsResponsiveness to a-GalCer stimulation was also assessed in 28 of the cancer patients and 37 of the healthy donors. Natural killer T cell numbers were significantly reduced in melanoma and breast cancer patients. While NKT numbers decreased with age in healthy donors, NKT cells were decreased in these cancer subgroups despite age and sex adjustments. Prior radiation treatment was shown to contribute to the observed reduction in melanoma patients. Although cancer patient NKT cells were significantly less responsive to a-GalCer stimulation, they remained capable of substantial expansion. Natural killer T cells are therefore modulated by age, malignancy and prior anticancer treatment; however, cancer patient NKT cells remain capable of responding to a-GalCer-based immenotherapies.

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“…Although these problems could in theory be largely overcome by mAbs specific for the semiinvariant TCR chains on NK T cells, this is not possible in practice, as anti-Vβ8.2 antibodies stain a large fraction of conventional T cells and the only published anti-Vα14 mAb 8 is of controversial specificity 1. The situation in humans is somewhat different, as mAbs against both Vα24 and Vβ11 exist 9. Nevertheless, only a fraction of all Vα24 + or Vβ11 + T cells are NK T cells, and even a double staining procedure to selectively identify Vα24 + Vβ11 + cells cannot exclude conventional T cells that rearrange Vα24 to J regions other than JαQ.…”

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confidence: 99%

Cd1d–Glycolipid Tetramers

MacDonald

2000

The Journal of Experimental Medicine

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An invariant V alpha 24-J alpha Q/V beta 11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells.

Cited by 410 publications

References 28 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

Modulation of human Vα24+Vβ11+ NKT cells by age, malignancy and conventional anticancer therapies

Cd1d–Glycolipid Tetramers

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