Invariant Natural Killer T Cells in Asthma and Chronic Obstructive Pulmonary Disease

Vijayanand, Pandurangan; Seumois, Grégory; Pickard, C.; Powell, Robert M.; Angco, Gilbert; Sammut, David; Gadola, Stephan D.; Friedmann, Peter S.; Djukanović, Ratko

doi:10.1056/nejmoa064691

Cited by 179 publications

(152 citation statements)

References 20 publications

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“…The role that innate‐like lymphocytes play in airways disease has evoked some controversy 61, 62, 63. Whereas iNKT cells are implicated in murine models of allergic airways disease, they are rare in the human airways;62 in comparison, MAIT cells are fivefold to tenfold more abundant in humans than in mice 27.…”

Section: Observations From Specific Diseasesmentioning

confidence: 99%

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

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SummaryMucosal‐associated invariant T (MAIT) cells are a novel class of innate‐like T cells, expressing a semi‐invariant T‐cell receptor (TCR) and able to recognize small molecules presented on the non‐polymorphic MHC‐related protein 1. Their intrinsic effector‐memory phenotype, enabling secretion of pro‐inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune‐mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation‐induced down‐regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR‐independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers.

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Section: Observations From Specific Diseasesmentioning

confidence: 99%

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

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“…Sputum samples were solubilized using dithioerythritol to allow separation of the cellular and fluid phases. Cell aliquots were then processed for flow cytometric analysis as previously reported (4).…”

Section: Acquisition Of Samples and Processingmentioning

confidence: 99%

“…The symptoms are thought to be the result of allergic inflammation of the airway, which is characterized by infiltrating eosinophils, mast cells, and basophils as prominent effector cells (2). T lymphocytes of the Th2 type (Th2 T cells), driven by chronic exposure to environmental airborne allergens, are increased in asthmatic airways and play a central role in orchestrating this inflammatory response by regulating IgE production, accumulation, and activation of eosinophils, as well as contributing to airway remodeling involving the epithelium and fibroblasts (3,4). The accumulation of Th2 T cells in the lungs is essential for both the initiation and persistence of airway inflammation (3), and studies in asthmatic volunteers have shown marked increases in Th2 T cells in the lungs after in vivo allergen challenge (5).…”

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confidence: 99%

Chemokine Receptor 4 Plays a Key Role in T Cell Recruitment into the Airways of Asthmatic Patients

Vijayanand

Durkin

Hartmann

et al. 2010

The Journal of Immunology

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“…The availability of multiple reagents active in various assays to identify and for manipulating iNKT cells will enable understanding their role in different patient population subsets (e.g. patients with various cancers [39], adult and pediatric acute versus chronic asthmatics, untreated or on various treatments [40][41][42][43][44][45]) and their various tissues, as well as intervening therapeutically. Given that several approaches to exploit iNKT cells have entered clinical trials [46,47], development of such a selective reagent seems timely.…”

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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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Invariant Natural Killer T Cells in Asthma and Chronic Obstructive Pulmonary Disease

Abstract: Invariant natural killer T cells are found in low numbers in the airways of subjects with asthma, subjects with COPD, and controls.

Cited by 179 publications

References 20 publications

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

Chemokine Receptor 4 Plays a Key Role in T Cell Recruitment into the Airways of Asthmatic Patients

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

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