A normal T cell receptor beta CDR3 length distribution in patients with APECED

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the AIRE gene. Murine studies suggest that AIRE controls thymic expression of tissue-restricted antigens, its absence allowing nonselected autoreactive cells to escape. We tested this in humans using the TCRβ CDR3 length repertoire as a surrogate of thymic selection, as it shortens during the process. Analysis of healthy thymuses showed an altogether 1.9 base pair shortening, starting at the CD4(+)CD8(+)CD3(low) stage and continuing until the CD4(+) subset, likely encompassing both the positive and negative selection. Comparison of five APECED patients with eight healthy controls showed a skewed repertoire with oligoclonal expansions in the patients' CD4(+) and CD8(+) populations. The average CDR3 length, however, was normal and unaffected by the skewing. This was also true of the hypothesized autoreactive CD8(+)CD45RA(+) population. We failed to detect a subset with an abnormally long CDR3 repertoire, as would be predicted by a failure in selection.