Glycolipid antigen induces long-term natural killer T cell anergy in mice

Parekh, Vrajesh V.; Wilson, Michael T.; Olivares–Villagómez, Danyvid; Singh, Avneesh K.; Wu, Lan; Wang, Chyung Ru; Joyce, Sebastian; Kaer, Luc Van

doi:10.1172/jci24762

Cited by 405 publications

(522 citation statements)

References 54 publications

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“…Autoimmunity prevention correlated with the ability of aGalCer to induce iNKT cell anergy and to strongly suppress their IFN-g production while IL-4 production was less inhibited [33]. Interestingly, we have observed that aGalCer treatment suppressed not only IFN-g by iNKT cells but also their IL-17 production whereas it does not inhibit IL-10 production (Fig.…”

Section: Cd4 à Inkt Cells Containing Inkt17 Cells Enhance the Incidenmentioning

confidence: 57%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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Section: Cd4 à Inkt Cells Containing Inkt17 Cells Enhance the Incidenmentioning

confidence: 57%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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“…As repeated NKT cell stimulation with free glycolipid is known to induce anergy, [36][37][38] we performed a dose response study using single injections of a-GalCer. A significant increase in overall survival time was observed with the highest dose (i.p.…”

Section: Glycolipid Treatments Reduce Metastasismentioning

confidence: 99%

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

et al. 2015

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Metastatic lesions are responsible for over 90% of breast cancer associated deaths. Therefore, strategies that target metastasis are of particular interest. This study examined the efficacy of natural killer T (NKT) cell activation as a postsurgical immunotherapy in a mouse model of metastatic breast cancer. Following surgical resection of orthotopic 4T1 mammary carcinoma tumors, BALB/c mice were treated with NKT cell activating glycolipid antigens (a-GalCer, a-CGalCer or OCH) or a-GalCer-loaded dendritic cells (DCs). Low doses of glycolipids transiently reduced metastasis but did not increase survival. A high dose of a-GalCer enhanced overall survival, but was associated with increased toxicity and mortality at early time points. Treatment with a-GalCer-loaded DCs limited tumor metastasis, prolonged survival, and provided curative outcomes in »45% of mice. However, survival was not increased further by additional DC treatments or co-transfer of expanded NKT cells. NKT cell activation via glycolipid-loaded DCs decreased the frequency and immunosuppressive activity of myeloid derived suppressor cells (MDSCs) in tumor-resected mice. In vitro, NKT cells were resistant to the immunosuppressive effects of MDSCs and were able to reverse the inhibitory effects of MDSCs on T cell proliferation. NKT cell activation enhanced antitumor immunity in tumor-resected mice, increasing 4T1-specific cytotoxic responses and IFNg production from natural killer (NK) cells and CD8 C T cells. Consistent with increased tumor immunity, mice surviving to day 150 were resistant to a second tumor challenge. This work provides a clear rationale for manipulating NKT cells to target metastatic disease.

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“…This would be in good agreement with the postulated role of the iNKT cell population as an 'innate' sensor of the immune system that links innate and adaptive immunity. Indeed, upon antigenic stimulation, iNKT cells expand for a few days and then quickly contract without generating memory cells [81].…”

Section: How Do Inkt Cells Get Activated? Cognate Recognition and Actmentioning

confidence: 99%

CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

Matsuda

Mallevaey

Scott‐Browne

et al. 2008

Current Opinion in Immunology

355

399

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SummaryNatural Killer T cells are a distinct lymphocyte lineage that regulates a broad range of immune responses. NKT cells recognize glycolipids presented by the non-classical MHC molecule CD1d. Structural insight into the TCR/glycolipid/CD1d tri-complex has revealed an unusual and unexpected mode of recognition. Recent studies have also identified some of the signaling events during NKT cell development that give NKT cells their innate phenotype. Pathogen-derived glycolipid antigens continue to be found, and new mechanisms of NKT cell activation have been described. Finally, NKT cells have been shown to be remarkably versatile in function during various immune responses. Whether these extensive functional capacities can be attributed to a single population sensitive to environmental cues or if functionally distinct NKT cell subpopulations exist remains unresolved.

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Glycolipid antigen induces long-term natural killer T cell anergy in mice

Cited by 405 publications

References 54 publications

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

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