Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells

J Clin Invest. 2004 Oct;114(7):979-87. doi: 10.1172/JCI20483.


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.

MeSH terms

  • Abatacept
  • Adoptive Transfer
  • Animals
  • Blood Glucose / metabolism
  • CD28 Antigens / genetics
  • CD28 Antigens / metabolism*
  • CD40 Antigens / genetics
  • CD40 Antigens / metabolism*
  • CD40 Ligand / genetics
  • CD40 Ligand / metabolism*
  • Cell Division
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Immunoconjugates / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / physiology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology*


  • Blood Glucose
  • CD28 Antigens
  • CD40 Antigens
  • Immunoconjugates
  • CD40 Ligand
  • Abatacept