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 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.
Arreaza
G A
GA
Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.
Cameron
M J
MJ
Jaramillo
A
A
Gill
B M
BM
Hardy
D
D
Laupland
K B
KB
Rapoport
M J
MJ
Zucker
P
P
Chakrabarti
S
S
Chensue
S W
SW
Qin
H Y
HY
Singh
B
B
Delovitch
T L
TL
D000818:Animals; D000831:Animals, Newborn; D018106:CD28 Antigens / Q000378:metabolism*; D002470:Cell Survival; D017635:Clonal Anergy; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D007116:Immunization, Passive; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D018106:CD28 Antigens; D007376:Interleukin-2; D015847:Interleukin-4; D005968:Glutamate Decarboxylase