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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 1997-11, Vol.100 (9), p.2243-2253
Main Authors: Arreaza, G A, Cameron, M J, Jaramillo, A, Gill, B M, Hardy, D, Laupland, K B, Rapoport, M J, Zucker, P, Chakrabarti, S, Chensue, S W, Qin, H Y, Singh, B, Delovitch, T L
Format: Article
Language:English
Subjects:
AIDS/HIV
Animals
Animals, Newborn
CD28 Antigens - metabolism
Cell Survival
Clonal Anergy
Diabetes Mellitus, Type 1 - immunology
Female
Glutamate Decarboxylase - immunology
Immunization, Passive
Interleukin-2 - biosynthesis
Interleukin-4 - physiology
Islets of Langerhans - immunology
Lymphocyte Activation
Mice
Mice, Inbred NOD
Signal Transduction
T-Lymphocytes - immunology
Th2 Cells - immunology
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Summary: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.
ISSN:0021-9738
DOI:10.1172/JCI119762