Type II NKT Cells: An Elusive Population With Immunoregulatory Properties

Singh, Avadhesh Kumar; Tripathi, Prabhanshu; Cardell, Susanna

doi:10.3389/fimmu.2018.01969

Cited by 76 publications

(71 citation statements)

References 86 publications

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“…Canonical Tregs express the transcription factor FoxP3, and their importance in maintaining self-tolerance is illustrated by Foxp3 mutation which results in fatal multi-organ autoimmune disease in both mice (scurfy mice) and humans (IPEX syndrome) [20]. However, non-canonical FoxP3regulatory CD4 + T cells [21,22] and other regulatory populations [23][24][25] have also been identified in a variety of contexts. RA is associated with reduced suppressive ability of Tregs, due to a Treg intrinsic defect as well as the inflammatory milieu [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

TRI microparticles prevent inflammatory arthritis in a collagen-induced arthritis model

et al. 2020

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Despite recent progress in the treatment of rheumatoid arthritis (RA), many patients still fail to achieve remission or low disease activity. An imbalance between auto-reactive effector T cells (Teff) and regulatory T cells (Treg) may contribute to joint inflammation and damage in RA. Therefore, restoring this balance is a promising approach for the treatment of inflammatory arthritis. Accordingly, our group has previously shown that the combination of TGF-βreleasing microparticles (MP), rapamycin-releasing MP, and IL-2-releasing MP (TRI MP) can effectively increase the ratio of Tregs to Teff in vivo and provide disease protection in several preclinical models. In this study TRI MP was evaluated in the collagen-induced arthritis (CIA) model. Although this formulation has been tested previously in models of destructive inflammation and transplantation, this is the first model of autoimmunity for which this therapy has been applied. In this context, TRI MP effectively reduced arthritis incidence, the severity of arthritis scores, and bone erosion. The proposed mechanism of action includes not only reducing CD4 + T cell proliferation, but also expanding a regulatory population in the periphery soon after TRI MP administration. These changes were reflected in the CD4 + T cell population that infiltrated the paws at the onset of arthritis and were associated with a reduction of immune infiltrate and inflammatory myeloid cells in the paws. TRI MP administration also reduced the titer of collagen antibodies, however the contribution of this reduced titer to disease protection remains uncertain since there was no correlation between collagen antibody titer and arthritis score.

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Section: Introductionmentioning

confidence: 99%

TRI microparticles prevent inflammatory arthritis in a collagen-induced arthritis model

et al. 2020

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“…Here we present the total synthesis of important microbial glycolipid antigens that can Most studies of NKT cells have focussed on the classical V14J18 + type I NKT cells, which is partly because of the use of the prototypic -GalCer glycolipid antigen that uniformly detects, and stimulates, these cells. The existence of other types of CD1d-restricted NKT cells (broadly defined as type II NKT cells) has been known for many years, 23 but a lack of knowledge of the specific lipid antigens to which they respond has limited investigations into the broader NKT cell family. In some cases lipid antigens such as sulfatide and phosphatidyl glycerol have been helpful for studying discrete subsets of these cells and more such studies are needed.…”

Section: Discussionmentioning

confidence: 99%

α-Glucuronosyl and α-Glucosyl Diacylglycerides, Natural Killer T Cell-Activating Lipids from Bacteria and Fungi

BURUGUPALLI¹,

ALMEIDA²,

Smith³

et al. 2019

Preprint

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Natural killer T cells express T cell receptors (TCRs) that recognize glycolipid antigens in association with the antigen-presenting molecule CD1d. Here, we report the concise chemical synthesis of a range of saturated and unsaturated α-glucosyl and α-glucuronosyl diacylglycerides of bacterial and fungal origins from allyl α-glucoside with Jacobsen kinetic resolution as a key step. We show that these glycolipids could be recognized by a classical type I NKT TCR that uses an invariant Vα14-Jα18 TCR α-chain, but also by an atypical NKT TCR that uses a different TCR α-chain (Vα10-Jα50). In both cases, recognition was sensitive to the lipid fine structure, and included recognition of glycosyl diacylglycerides bearing branched (R- and S-tuberculostearic acid) and unsaturated (oleic and vaccenic) acids. The TCR footprints on CD1d-loaded with a mycobacterial α-glucuronosyl diacylglyceride was assessed using mutant CD1d molecules and, while similar to that for α-GalCer recognition by a type I NKT TCR, were more sensitive to mutations when α-glucuronosyl diacylglyceride was the antigen. In summary, we provide an efficient approach for synthesis of a broad class of bacterial and fungal α-glycosyl diacylglyceride antigens and demonstrate that they can be recognised by TCRs derived from type I and atypical NKT cells.

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“…Type I NKT cells, which is the most extensively studied subgroup, express a semi‐invariant Vα14‐Jα18 TCR in mice and Vα24‐Jα18 in humans, paired with diverse TCR β‐chains using Vβ8.2, Vβ7 and Vβ2 in mice and Vβ11 in humans . The less explored type II NKT cells utilize a diverse TCR repertoire both in mice and humans …”

Section: Introductionmentioning

confidence: 99%

“…This has been instrumental for generating detailed information on type I NKT cells and has helped to establish an immunoregulatory role of these cells. In contrast, type II NKT cells recognize a diverse repertoire of lipid antigens, and as for today, no unique cell surface marker has been identified for this subset, making broad studies of type II NKT cells difficult . Significant information has been provided by studies of a transgenic mouse expressing a type II NKT cell TCR .…”

Section: Introductionmentioning

confidence: 99%

“…Further, type II NKT cells express the transcription factor PLZF, required for the development of type I NKT cells . Although transgenic 24αβ type II NKT cells share many features with type I NKT cells, 24αβ type II NKT cells exhibit other phenotypic traits (CD62L hi , CD69 neg/lo and CD49b + ), effector molecules (production of IFN‐γ rather than IL‐4), NK receptors, integrins and chemokine receptors distinct from type I NKT cells . This suggested that at least some type II NKT cells might preferentially be TH1‐like and have a naive/resting phenotype, while type I NKT cells produce a broader cytokine array and have an activated memory‐like phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Defining a novel subset of CD1d‐dependent type II natural killer T cells using natural killer cell‐associated markers

et al. 2019

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Natural killer T (NKT) cells are αβ T cell receptor (TCR) expressing innate‐like T cells that display natural killer (NK) cell markers. Based on TCR characteristics, they are divided into two groups restricted to the MHC class I‐like molecule CD1d. Type I NKT cells, most extensively studied, are identified by a semi‐invariant Vα14‐Jα18 (mouse, Vα24‐Jα18 in humans) TCR reactive to the prototypic ligand α‐galactosylceramide presented on CD1d. In contrast, type II NKT cells display diverse TCR reacting to different CD1d‐presented ligands. There are no reagents that identify all type II NKT cells, limiting their exploration. Here, we searched for novel type II NKT cells by comparing Jα18−/−MHCII−/− mice that harbour type II but not type I NKT cells, and CD1d−/−MHCII−/− mice, lacking all NKT cells. We identified significantly larger populations of CD4+ and CD4−CD8− (double negative, DN) TCRβ+ cells expressing NKG2D or NKG2A/C/E in Jα18−/−MHCII−/− mice compared with CD1d−/−MHCII−/− mice, suggesting that 30%‐50% of these cells were type II NKT cells. They expressed CD122, NK1.1, CXCR3 and intermediate/low levels of CD45RB. Further, the CD4+ subset was CD69+, while the DN cells were CD49b+ and CD62L+. Both subsets expressed the NKT cell‐associated promyelocytic leukaemia zinc finger (PLZF) transcription factor and Tbet, while fewer cells expressed RORγt. NKG2D+ CD4+ and DN populations were producers of IFN‐γ, but rarely IL‐4 and IL‐17. Taken together, we identify a novel subset of primary CD4+ and DN type II NKT cells that expresses NKG2 receptors have typical NKT cell phenotypes and a TH1‐like cytokine production.

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Type II NKT Cells: An Elusive Population With Immunoregulatory Properties

Cited by 76 publications

References 86 publications

TRI microparticles prevent inflammatory arthritis in a collagen-induced arthritis model

TRI microparticles prevent inflammatory arthritis in a collagen-induced arthritis model

α-Glucuronosyl and α-Glucosyl Diacylglycerides, Natural Killer T Cell-Activating Lipids from Bacteria and Fungi

Defining a novel subset of CD1d‐dependent type II natural killer T cells using natural killer cell‐associated markers

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