OVEREXPRESSION OF THE FOSB2 GENE IN THYMOCYTES CAUSES ABERRANT DEVELOPMENT OF T-CELLS AND THYMIC EPITHELIAL-CELLS

We have examined the role of the AP-1 transcription factor on thymocyt e maturation and thymus architecture by overexpressing FosB2 in transg enic mice. FosB2 is a naturally occurring splice variant of the FosB2 gene, encoding a truncated protein which lacks two domains necessary f or transcriptional activation. The expression of FosB2 in the thymocyt es severely affected their maturation and the structure of the whole t hymus: the phenotype developed slowly during the first months of life, resulting in a progressive expansion of the medulla and concomitant r eduction of the cortex. CD4(+) thymocytes represented the major thymoc yte population, whereas the CD4(+)8(+) thymocytes were virtually absen t. This phenotype appeared to be an intrinsic property of bone marrow derived cells, as it could be reproduced in bone marrow chimaeric mice , This pathology was very reminiscent to that observed in mice overexp ressing c-Fos in thymic epithelium: also in that case the thymus under went with age a progressive expansion of the epithelium and major chan ges in the ratio of thymocyte subsets, but the phenotype appeared to b e an intrinsic property of the epithelial cells since it could not be reproduced by transgenic bone marrow transplantation. We speculate tha t both overexpression of FosB2 in thymocytes and overexpression of c-F os in thymic epithelium results in aberrant signaling between thymocyt es and stroma, that ultimately alters the thymic micromilieu, leading to this severe pathology.