Apoptosis during negative selection of autoreactive thymocytes

Curr Opin Immunol. 2007 Oct;19(5):510-5. doi: 10.1016/j.coi.2007.06.001. Epub 2007 Jul 25.


Recent investigations have solidified the importance of negative selection in controlling autoimmunity. Loss of autoimmune regulator (AIRE), required for thymic stromal-cell differentiation and thymic expression of peripheral antigens, results in multi-organ autoimmunity. Mice with AIRE/Foxp3 double mutations suffer from exacerbated autoimmunity when compared with mice with only one mutation, supporting the important contributions of both central and peripheral tolerance. In thymocytes, Cbl is a negative regulator of thymocyte apoptosis while MINK, a MEKK kinase, is required for negative selection. This is consistent with the requirement of JNK, p38 and possibly ERK5 MAP kinases in thymocyte apoptosis. ERK5 induces the Nur77 orphan steroid receptor family members. In cell lines, Nur77 interaction with Bcl-2 turns Bcl-2 into a pro-apoptotic molecule. This and other possibilities will be discussed to explain the unresolved finding that negative selection is defective in Bim(-/-) but is not efficiently blocked in Bcl-2 transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Autoimmunity*
  • Bcl-2-Like Protein 11
  • Clonal Deletion
  • Humans
  • Membrane Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Self Tolerance*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Thymus Gland / metabolism
  • Transcription Factors / metabolism*


  • APECED protein
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factors