Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells.
The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse results from a breakdown in tolerance to pancreatic islet antigens. CD28-B7 and CD40 ligand-CD40 (CD40L-CD40) costimulatory pathways affect the development of disease and are promising therapeutic targets. Indeed, it was shown previously that diabetes fails to develop in NOD-B7-2-/- and NOD-CD40L-/- mice. In this study, we examined the relative role of these 2 costimulatory pathways in the balance of autoimmunity versus regulation in NOD mice. We demonstrate that initiation but not effector function of autoreactive T cells was defective in NOD-B7-2-/- mice. Moreover, the residual proliferation of the autoreactive cells was effectively controlled by CD28-dependent CD4+CD25+ regulatory T cells (Treg's), as depletion of Treg's partially restored proliferation of autoreactive T cells and resulted in diabetes in an adoptive-transfer model. Similarly, disruption of the CD28-B7 pathway and subsequent Treg deletion restored autoimmunity in NOD-CD40L-/- mice. These results demonstrate that development of diabetes is dependent on a balance of pathogenic and regulatory T cells that is controlled by costimulatory signals. Thus, elimination of Treg's results in diabetes even in the absence of costimulation, which suggests a need for alternative strategies for immunotherapeutic approaches.
UCSF Diabetes Center, University of California at San Francisco, San Francisco, California 94143, USA.
Hélène
H
Bour-Jordan
Benoît L
BL
Salomon
Heather L
HL
Thompson
Gregory L
GL
Szot
Matthew R
MR
Bernhard
Jeffrey A
JA
Bluestone
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018796:Immunoconjugates / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
D001786:Blood Glucose; D018106:CD28 Antigens; D019013:CD40 Antigens; D018796:Immunoconjugates; D023201:CD40 Ligand; D000069594:Abatacept