BIM Deficiency Protects NOD Mice From Diabetes by Diverting Thymocytes to Regulatory T Cells

Diabetes. 2015 Sep;64(9):3229-38. doi: 10.2337/db14-1851. Epub 2015 May 6.


Because regulatory T-cell (Treg) development can be induced by the same agonist self-antigens that induce negative selection, perturbation of apoptosis will affect both negative selection and Treg development. But how the processes of thymocyte deletion versus Treg differentiation bifurcate and their relative importance for tolerance have not been studied in spontaneous organ-specific autoimmune disease. We addressed these questions by removing a critical mediator of thymocyte deletion, BIM, in the NOD mouse model of autoimmune diabetes. Despite substantial defects in the deletion of autoreactive thymocytes, BIM-deficient NOD (NODBim(-/-)) mice developed less insulitis and were protected from diabetes. BIM deficiency did not impair effector T-cell function; however, NODBim(-/-) mice had increased numbers of Tregs, including those specific for proinsulin, in the thymus and peripheral lymphoid tissues. Increased levels of Nur77, CD5, GITR, and phosphorylated IκB-α in thymocytes from NODBim(-/-) mice suggest that autoreactive cells receiving strong T-cell receptor signals that would normally delete them escape apoptosis and are diverted into the Treg pathway. Paradoxically, in the NOD model, reduced thymic deletion ameliorates autoimmune diabetes by increasing Tregs. Thus, modulating apoptosis may be one of the ways to increase antigen-specific Tregs and prevent autoimmune disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / immunology
  • Bcl-2-Like Protein 11
  • CD5 Antigens / metabolism
  • Clonal Deletion / genetics*
  • Clonal Deletion / immunology
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Disease Models, Animal
  • Glucocorticoid-Induced TNFR-Related Protein / metabolism
  • I-kappa B Proteins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred NOD
  • NF-KappaB Inhibitor alpha
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Thymocytes / immunology*
  • Thymocytes / metabolism


  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • CD5 Antigens
  • Cd5 protein, mouse
  • Glucocorticoid-Induced TNFR-Related Protein
  • I-kappa B Proteins
  • Membrane Proteins
  • Nfkbia protein, mouse
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Proto-Oncogene Proteins
  • Tnfrsf18 protein, mouse
  • NF-KappaB Inhibitor alpha