Saturday, November 7, 2015

Fezl ascends to the thymic throne as Aire's equal and co-ruler

A thymus controls T cell development and central tolerance. It first selects newborn T cells capable of recognizing MHC molecules and then purges those T cells who interact with MHC + self peptide complexes too strongly

But what about self-antigens that are physiologically expressed in peripheral tissue, such as insulin (endocrine), neuronal antigens (CNS), testis and ovary antigens (reproductive)? Initially, it was assumed that mechanism called "'peripheral tolerance" was responsible for elimination of peripheral antigen-specific T cells. But later, it was shown that protein called Aire controlled expression some of the tissue-restricted antigens (TRAs) in the thymus thus facilitating central tolerance to those peripheral antigens. Interestingly, analysis of Aire KO thymus had shown that there were Aire-independent TRAs expressed in the thymus, implying the existence of yet unknown mechanism.

Now, new Cell paper revealed the identity of molecule responsible for Aire-independent TRAs expression. It turned out that thymic protein Fezf2, also known as Fezl, was responsible for expression of unique set of TRAs in the thymus independently of Aire.   

First, the authors found that Fezl was highly expressed in mTECs, thymic cells responsible for central tolerance.

Role of Fezl in tolerance was tested in nude mice lacking endogenous thymus. Nude mice receiving Fezl KO thymic transplantation developed peripheral tissue immunopathology [because TRAs-specific T cells were not deleted].

At the same time, the authors showed that Aire's expression was not altered by absence of Fezl.

Expression pattern of TRAs in thymus revealed that Aire and Fezl mostly controlled non-overlapping set of TRAs.

Experiments with thymic-specific Fezl deficiency showed peripheral lymphoid tissue enlargement and autoantibody development.

Finally, the authors found that unlike Aire, Fezl expression was controlled by lymphotoxin beta receptor (LtβR) pathway.

In summary, this truly breakthrough study revealed a new dimension for thymic TRAs expression. Mutations in Fezl could underlie some of the known forms of immunopathology.

David Usharauli

No comments:

Post a Comment