Apoptosis during negative selection of autoreactive thymocytes

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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.

Introduction

During development, autoreactive thymocytes are eliminated through apoptosis in a process termed negative selection (central tolerance). This process has always been thought to be important to prevent autoimmunity, but concrete proof did not come until recently. Indeed, given that mice possessing mutations in the Fas, IL-2, or Foxp3 gene develop severe autoimmunity despite normal negative selection, some have argued that peripheral tolerance is more important than central tolerance and that T cell negative selection might be dispensable for development of a normal immune system (for example, see [1]). This argument was bolstered by examples of apparently little or no autoimmunity and only a partial inhibition of thymocyte apoptosis in mice harboring a mutation in a single gene involved in negative selection. Nonetheless, the identification of autoimmune regulator (AIRE) as a protein important for expression of non-thymic antigens on stromal cells has started to bring credence to the importance of negative selection [2]. AIRE-deficient mice suffer from multiple organ autoimmunity. In this review, we will discuss AIRE and its importance in thymic stromal cells. In addition, we will discuss advances in our understanding of how T cells might distinguish positive from negative selection signals. Recent elucidation of signaling proteins important for negative selection in T cells will be reviewed.

Section snippets

AIRE, thymic epithelial cells, and the importance of central tolerance

AIRE was first identified as a gene defective in human patients suffering from multiple organ autoimmunity autoimmune polyendocrinopathy (APECED) [3, 4]. Similar to human APECED patients, AIRE-deficient mice exhibit autoimmunity in multiple organs [2]. AIRE is primarily expressed in medullary thymic epithelial cells (mTECs). Interestingly, mTECs express many ‘tissue-specific antigens’ usually not found in thymocytes or T cells. Expression of these antigens is lost in AIRE−/− mTEC. Subsequent

Signaling molecules regulating negative selection

Cbl proteins are ubiquitin ligases thought to negatively regulate TCR signaling. Inactivation of both c-Cbl and Cbl-b, two of the Cbl family members, leads to enhanced negative selection [14]. In female H-Y TCR transgenic mice, where the majority of thymocytes normally undergo positive selection to become CD8+ cells, depletion of CD4+CD8+ double-positive (DP) thymocytes was instead noted in c-Cbl/Cbl-b double-deficient background. Interestingly, although most membrane-proximal events are

If Bim is the only BH3 molecule involved in negative selection, why is Bcl-2 overexpression unable to efficiently inhibit negative selection?

The NOD strain of mice suffers from diabetes. This is partly because of defective negative selection. Using DNA microarray analysis, two groups have examined the gene expression profiles of wild-type and NOD mice. Both groups have identified Bim and Nur77 among genes that are upregulated in stimulated wild-type but not NOD CD4+CD8+ thymocytes [28, 29, 30]. These results are consistent with previous functional studies for the roles of Bim and Nur77 family in negative selection [31, 32, 33, 34].

Conclusions

As evidenced by the genetic data, central and peripheral tolerance work together to prevent autoimmune diseases. The observation that Bim and Nur77 levels are suppressed in thymocytes in multiple autoimmune disease models, although mostly correlative, render further support for their roles in negative selection. With the potential for Bcl-2 to act as a pro-apoptotic molecule, we can now consider a modified model wherein Bim/Bcl-2 pathway functionally, and perhaps synergistically, interacts with

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

Work in this laboratory is supported by grants from the National Institutes of Health.

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