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Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes

Reactive oxygen species (ROS) play prominent roles in numerous biological systems. While classically expressed by neutrophils and macrophages, CD4 T cells also express NADPH oxidase (NOX), the superoxide-generating multisubunit enzyme. Our laboratory recently demonstrated that superoxide-deficient n...

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Autores principales: Padgett, Lindsey E., Anderson, Brian, Liu, Chao, Ganini, Douglas, Mason, Ronald P., Piganelli, Jon D., Mathews, Clayton E., Tse, Hubert M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657579/
https://www.ncbi.nlm.nih.gov/pubmed/26269022
http://dx.doi.org/10.2337/db15-0546
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author Padgett, Lindsey E.
Anderson, Brian
Liu, Chao
Ganini, Douglas
Mason, Ronald P.
Piganelli, Jon D.
Mathews, Clayton E.
Tse, Hubert M.
author_facet Padgett, Lindsey E.
Anderson, Brian
Liu, Chao
Ganini, Douglas
Mason, Ronald P.
Piganelli, Jon D.
Mathews, Clayton E.
Tse, Hubert M.
author_sort Padgett, Lindsey E.
collection PubMed
description Reactive oxygen species (ROS) play prominent roles in numerous biological systems. While classically expressed by neutrophils and macrophages, CD4 T cells also express NADPH oxidase (NOX), the superoxide-generating multisubunit enzyme. Our laboratory recently demonstrated that superoxide-deficient nonobese diabetic (NOD.Ncf1(m1J)) mice exhibited a delay in type 1 diabetes (T1D) partially due to blunted IFN-γ synthesis by CD4 T cells. For further investigation of the roles of superoxide on CD4 T-cell diabetogenicity, the NOD.BDC-2.5.Ncf1(m1J) (BDC-2.5.Ncf1(m1J)) mouse strain was generated, possessing autoreactive CD4 T cells deficient in NOX-derived superoxide. Unlike NOD.Ncf1(m1J), stimulated BDC-2.5.Ncf1(m1J) CD4 T cells and splenocytes displayed elevated synthesis of Th1 cytokines and chemokines. Superoxide-deficient BDC-2.5 mice developed spontaneous T1D, and CD4 T cells were more diabetogenic upon adoptive transfer into NOD.Rag recipients due to a skewing toward impaired Treg suppression. Exogenous superoxide blunted exacerbated Th1 cytokines and proinflammatory chemokines to approximately wild-type levels, concomitant with reduced IL-12Rβ2 signaling and P-STAT4 (Y693) activation. These results highlight the importance of NOX-derived superoxide in curbing autoreactivity due, in part, to control of Treg function and as a redox-dependent checkpoint of effector T-cell responses. Ultimately, our studies reveal the complexities of free radicals in CD4 T-cell responses.
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spelling pubmed-46575792016-12-01 Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes Padgett, Lindsey E. Anderson, Brian Liu, Chao Ganini, Douglas Mason, Ronald P. Piganelli, Jon D. Mathews, Clayton E. Tse, Hubert M. Diabetes Immunology and Transplantation Reactive oxygen species (ROS) play prominent roles in numerous biological systems. While classically expressed by neutrophils and macrophages, CD4 T cells also express NADPH oxidase (NOX), the superoxide-generating multisubunit enzyme. Our laboratory recently demonstrated that superoxide-deficient nonobese diabetic (NOD.Ncf1(m1J)) mice exhibited a delay in type 1 diabetes (T1D) partially due to blunted IFN-γ synthesis by CD4 T cells. For further investigation of the roles of superoxide on CD4 T-cell diabetogenicity, the NOD.BDC-2.5.Ncf1(m1J) (BDC-2.5.Ncf1(m1J)) mouse strain was generated, possessing autoreactive CD4 T cells deficient in NOX-derived superoxide. Unlike NOD.Ncf1(m1J), stimulated BDC-2.5.Ncf1(m1J) CD4 T cells and splenocytes displayed elevated synthesis of Th1 cytokines and chemokines. Superoxide-deficient BDC-2.5 mice developed spontaneous T1D, and CD4 T cells were more diabetogenic upon adoptive transfer into NOD.Rag recipients due to a skewing toward impaired Treg suppression. Exogenous superoxide blunted exacerbated Th1 cytokines and proinflammatory chemokines to approximately wild-type levels, concomitant with reduced IL-12Rβ2 signaling and P-STAT4 (Y693) activation. These results highlight the importance of NOX-derived superoxide in curbing autoreactivity due, in part, to control of Treg function and as a redox-dependent checkpoint of effector T-cell responses. Ultimately, our studies reveal the complexities of free radicals in CD4 T-cell responses. American Diabetes Association 2015-12 2015-08-12 /pmc/articles/PMC4657579/ /pubmed/26269022 http://dx.doi.org/10.2337/db15-0546 Text en © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Immunology and Transplantation
Padgett, Lindsey E.
Anderson, Brian
Liu, Chao
Ganini, Douglas
Mason, Ronald P.
Piganelli, Jon D.
Mathews, Clayton E.
Tse, Hubert M.
Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes
title Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes
title_full Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes
title_fullStr Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes
title_full_unstemmed Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes
title_short Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes
title_sort loss of nox-derived superoxide exacerbates diabetogenic cd4 t-cell effector responses in type 1 diabetes
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657579/
https://www.ncbi.nlm.nih.gov/pubmed/26269022
http://dx.doi.org/10.2337/db15-0546
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