Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population
- Coquet, Jonathan, Chakravarti, Sumone, Kyparissoudis, Konstantinos, McNab, Finlay, Pitt, Lauren, McKenzie, Brent, Berzins, Stuart, Smyth, Mark, Godfrey, Dale
- Authors: Coquet, Jonathan , Chakravarti, Sumone , Kyparissoudis, Konstantinos , McNab, Finlay , Pitt, Lauren , McKenzie, Brent , Berzins, Stuart , Smyth, Mark , Godfrey, Dale
- Date: 2008
- Type: Text , Journal article
- Relation: Proceedings of the National Academy of Sciences of the United States of America Vol. 105, no. 32 (August 2008 2008), p. 11287-11292
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- Description: NKT cell subsets can be divided based on CD4 and NK1.1 expression and tissue of origin, but the developmental and functional relationships between the different subsets still are poorly understood. A comprehensive study of 19 cytokines across different NKT cell subsets revealed that no two NKT subpopulations exhibited the same cytokine profile, and, remarkably, the amounts of each cytokine produced varied by up to 100-fold or more among subsets. This study also revealed the existence of a population of CD4-NK1.1 - NKT cells that produce high levels of the proinflammatory cytokine IL-17 within 2-3 h of activation. On intrathymic transfer these cells develop into mature CD4-NK1.1+ but not into CD4 +NK1.1+ NKT cells, indicating that CD4-NK1. 1- NKT cells include an IL-17-producing subpopulation, and also mark the elusive branch point for CD4+ and CD4- NKT cell sublineages.
- Description: C1
- Authors: Coquet, Jonathan , Chakravarti, Sumone , Kyparissoudis, Konstantinos , McNab, Finlay , Pitt, Lauren , McKenzie, Brent , Berzins, Stuart , Smyth, Mark , Godfrey, Dale
- Date: 2008
- Type: Text , Journal article
- Relation: Proceedings of the National Academy of Sciences of the United States of America Vol. 105, no. 32 (August 2008 2008), p. 11287-11292
- Full Text:
- Reviewed:
- Description: NKT cell subsets can be divided based on CD4 and NK1.1 expression and tissue of origin, but the developmental and functional relationships between the different subsets still are poorly understood. A comprehensive study of 19 cytokines across different NKT cell subsets revealed that no two NKT subpopulations exhibited the same cytokine profile, and, remarkably, the amounts of each cytokine produced varied by up to 100-fold or more among subsets. This study also revealed the existence of a population of CD4-NK1.1 - NKT cells that produce high levels of the proinflammatory cytokine IL-17 within 2-3 h of activation. On intrathymic transfer these cells develop into mature CD4-NK1.1+ but not into CD4 +NK1.1+ NKT cells, indicating that CD4-NK1. 1- NKT cells include an IL-17-producing subpopulation, and also mark the elusive branch point for CD4+ and CD4- NKT cell sublineages.
- Description: C1
NKT cell development in the absence of the autoimmune regulator gene (Aire)
- Pitt, Lauren, Hubert, Francois-Xavier, Scott, Hamish, Godfrey, Dale, Berzins, Stuart
- Authors: Pitt, Lauren , Hubert, Francois-Xavier , Scott, Hamish , Godfrey, Dale , Berzins, Stuart
- Date: 2008
- Type: Text , Journal article
- Relation: European Journal of Immunology Vol. 38, no. 10 (2008), p. 2689-2696
- Full Text: false
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- Description: Autoimmune regulator gene (Aire)-deficient mice develop an array of autoimmune lesions that reflect failures of immune tolerance. Negative selection is clearly compromised in these mice, but there is evidence to suggest that other mechanisms of tolerance might also be affected, including a possible impairment of regulatory T cell (Treg) development. Studies to date have failed to demonstrate any significant impact on the development or function of the FOXP31 Treg compartment, but NKT cells represent a distinct regulatory cell lineage that also develop in the thymus and which are known to influence self-tolerance. Aire-related defects coincide with NKT cell deficiencies in a number of animal models, but the direct consequence of Aire-deficiency on NKT cell development has not been established. In this study, we demonstrate that the frequency, distribution and cytokine production of NKT cells and their subsets is principally normal in Aire-deficient mice. We conclude that Aire has little or no effect on regulatory T cell development in general and NKT cells in particular.
- Description: C1
Temporal regulation of natural Killer T cell interferon gamma responses by β-catenin-dependent and -independent Wnt signaling
- Kling, Jessica, Jordan, Margaret, Pitt, Lauren, Meiners, Jana, Thanh-Tran, Thao, Tran, Le Son, Nguyen, Tam, Mittal, Deepak, Villani, Rehan, Steptoe, Raymond, Khosrotehrani, Kiarash, Berzins, Stuart, Baxter, Alan, Godrey, Dale, Blumental, Antje
- Authors: Kling, Jessica , Jordan, Margaret , Pitt, Lauren , Meiners, Jana , Thanh-Tran, Thao , Tran, Le Son , Nguyen, Tam , Mittal, Deepak , Villani, Rehan , Steptoe, Raymond , Khosrotehrani, Kiarash , Berzins, Stuart , Baxter, Alan , Godrey, Dale , Blumental, Antje
- Date: 2018
- Type: Text , Journal article
- Relation: Frontiers in Immunology Vol. 9, no. (2018), p. 1-13
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- Reviewed:
- Description: Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-γ) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator β-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-γ production. β-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and β-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, α-galactosylceramide (α-GalCer) using a mouse model. Pharmacologic targeting of β-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-γ responses. By contrast, within several hours of α-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired α-GalCer-induced IFN-γ responses, independent of β-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/β-catenin signaling that curbs IFN-γ responses, but that, subsequently, Wnt ligands sustain IFN-γ expression independent of β-catenin activity. Our analyses in ICG001-treated mice confirmed a role for β-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to α-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and β-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of β-catenin to NKT cell functions.
- Description: Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-
- Authors: Kling, Jessica , Jordan, Margaret , Pitt, Lauren , Meiners, Jana , Thanh-Tran, Thao , Tran, Le Son , Nguyen, Tam , Mittal, Deepak , Villani, Rehan , Steptoe, Raymond , Khosrotehrani, Kiarash , Berzins, Stuart , Baxter, Alan , Godrey, Dale , Blumental, Antje
- Date: 2018
- Type: Text , Journal article
- Relation: Frontiers in Immunology Vol. 9, no. (2018), p. 1-13
- Full Text:
- Reviewed:
- Description: Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-γ) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator β-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-γ production. β-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and β-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, α-galactosylceramide (α-GalCer) using a mouse model. Pharmacologic targeting of β-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-γ responses. By contrast, within several hours of α-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired α-GalCer-induced IFN-γ responses, independent of β-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/β-catenin signaling that curbs IFN-γ responses, but that, subsequently, Wnt ligands sustain IFN-γ expression independent of β-catenin activity. Our analyses in ICG001-treated mice confirmed a role for β-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to α-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and β-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of β-catenin to NKT cell functions.
- Description: Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-
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