Selective reduction of T cells bearing invariant V alpha 24J alpha Q antigen receptor in patients with systemic sclerosis.

Sumida, Takayuki; Sakamoto, Akemi; Murata, Hideyuki; Makino, Yuko; Takahashi, Hidenori; Yoshida, Sho; Nishioka, Kusuki; Iwamoto, Itsuo; Taniguchi, Masaru

doi:10.1084/jem.182.4.1163

Cited by 289 publications

(191 citation statements)

References 21 publications

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“…Some women could be more susceptible to autoimmune disease in part because of increased NKT cell numbers. However, this possibility seems unlikely given that these cells are depleted or skewed in patients with systemic sclerosis and multiple sclerosis [17,18], and can be protective in murine models of diabetes [32][33][34][35]. A more likely scenario is that the number of regulatory and protective V § 24 NKT cells may be expanded in some women to control a sex-dependent predisposition to some autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

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Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Vα24 NKT cell compartment

2003

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V § 24 natural killer T (NKT) cells are innate immune cells that recognize self and nonself glycolipids presented by CD1d molecules, and play immunoregulatory roles in autoimmunity and tumor immunity. We have investigated the circulating V § 24 NKT cells in a large cohort of human subjects. CCR7 -CD45RO + effector memory cells dominated both CD4 + and CD4 -NKT subsets, while a minority displayed a central memory phenotype. CD4 -central memory NKT cells, however, were atypical in that they largely lacked CD62L expression. Overall, CD4 -NKT cells displayed a functional phenotype with effector characteristics, while the CD4 + subset appeared immunoregulatory. Interestingly, NKT cell numbers in blood varied widely between subjects, and elevated numbers of these cells were much more common in women than in men. The CD4 + subset dominated the NKT cell compartment in both sexes, while circulating NKT cell numbers above 0.1% were associated with an expanded CD4 -subset. Although NKT cell numbers were generally stable over time, we describe a dynamic fivefold expansion that was associated with a skewing of the NKT CD4 + :CD4 -ratio that persisted after numbers returned to base line. Thus, the two NKT cell subsets display different properties and dynamics that will influence their function as innate immunoregulatory and effector cells.

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Section: Discussionmentioning

confidence: 99%

“…In one study, systemic sclerosis patients had a selective reduction of CD4 -8 -V § 24 NKT cells, while other CD4 -8 -T cells were increased [17]. The number of circulating V § 24 NKT cells can be reduced in patients with multiple sclerosis [18], systemic lupus erythematosus [19], and rheumatoid arthritis [20].…”

Section: Introductionmentioning

confidence: 99%

Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Vα24 NKT cell compartment

2003

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“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

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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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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“…In mouse models, NKT cells can suppress a number of different autoimmune diseases [4], including type 1 diabetes and experimental autoimmune encephalitis (EAE), yet also enhance pro-inflammatory immune responses that promote tumor rejection and clearance of some microbial infections [5][6][7]. Several studies have linked NKT cell deficiencies with cancer and autoimmune disease in humans [8][9][10][11], with a few exceptions [12]. In NKT cell-deficient NOD mice, the systemic NKT cell deficiency appears to originate in the thymus [13], but whether the highly variable frequency of NKT cells in human blood is also linked to NKT cell levels in the thymus is unknown, because no human studies have directly compared thymus and blood NKT cells from the same donors.…”

Section: Introductionmentioning

confidence: 99%

Limited correlation between human thymus and blood NKT cell content revealed by an ontogeny study of paired tissue samples

et al. 2005

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NKT cells are a CD1d-restricted T cell subset with strong immunoregulatory properties. Human NKT deficiencies are associated with autoimmune diseases such as type 1 diabetes and several types of cancer, yet there is little understanding of how the human NKT cell pool develops or is maintained. In this study, we present the first detailed analysis of human NKT cells from donor-matched postnatal thymus and blood samples. In mice, NKT cells are a thymus-dependent population that migrates to the periphery at an immature stage. Our data show that human NKT cells also undergo early stages of development in the thymus, forming a CD4 + CD161 -/low population that predominates neonatal thymic and blood NKT cell pools. CD4 -and CD161 + NKT cells accumulate with age in the blood, but not thymus, to the point that they dominate the NKT cell compartment in adult blood. This is consistent with the post-thymic maturation of NKT cells exported from the thymus at the putatively immature CD4 + CD161 -/low stage. Interestingly, while thymus and peripheral NKT cell frequencies vary widely between patients and are relatively stable between age groups, there is no clear relationship between the NKT cell frequency in thymus and blood.

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Selective reduction of T cells bearing invariant V alpha 24J alpha Q antigen receptor in patients with systemic sclerosis.

Cited by 289 publications

References 21 publications

Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Vα24 NKT cell compartment

Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Vα24 NKT cell compartment

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

Limited correlation between human thymus and blood NKT cell content revealed by an ontogeny study of paired tissue samples

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