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Research Article Free access | 10.1172/JCI119762

Neonatal activation of CD28 signaling overcomes T cell anergy and prevents autoimmune diabetes by an IL-4-dependent mechanism.

G A Arreaza, M J Cameron, A Jaramillo, B M Gill, D Hardy, K B Laupland, M J Rapoport, P Zucker, S Chakrabarti, S W Chensue, H Y Qin, B Singh, and T L Delovitch

Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

Find articles by Singh, B. in: PubMed | Google Scholar

Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.

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Published November 1, 1997 - More info

Published in Volume 100, Issue 9 on November 1, 1997
J Clin Invest. 1997;100(9):2243–2253. https://doi.org/10.1172/JCI119762.
© 1997 The American Society for Clinical Investigation
Published November 1, 1997 - Version history
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Abstract

Optimal T cell responsiveness requires signaling through the T cell receptor (TCR) and CD28 costimulatory receptors. Previously, we showed that T cells from autoimmune nonobese diabetic (NOD) mice display proliferative hyporesponsiveness to TCR stimulation, which may be causal to the development of insulin-dependent diabetes mellitus (IDDM). Here, we demonstrate that anti-CD28 mAb stimulation restores complete NOD T cell proliferative responsiveness by augmentation of IL-4 production. Whereas neonatal treatment of NOD mice with anti-CD28 beginning at 2 wk of age inhibits destructive insulitis and protects against IDDM by enhancement of IL-4 production by islet-infiltrating T cells, administration of anti-CD28 beginning at 5-6 wk of age does not prevent IDDM. Simultaneous anti-IL-4 treatment abrogates the preventative effect of anti-CD28 treatment. Thus, neonatal CD28 costimulation during 2-4 wk of age is required to prevent IDDM, and is mediated by the generation of a Th2 cell-enriched nondestructive environment in the pancreatic islets of treated NOD mice. Our data support the hypothesis that a CD28 signal is requisite for activation of IL-4-producing cells and protection from IDDM.

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