TRANSGENE-ENCODED HUMAN CD2 ACTS IN A DOMINANT-NEGATIVE FASHION TO MODIFY THYMOCYTE SELECTION SIGNALS IN MICE

CD2 is a cell surface glycoprotein present on all T cells which has be en shown to function as an adhesion and signaling molecule. Expressed early in T cell development, human CD2 (HCD2) has been suggested to pl ay a role during thymopoiesis. However, the relevance of CD2 in T cell development has been called into question recently, as neither disrup tion of the CD2 gene nor anti-CD2 antibody treatment of fetal thymic o rgan cultures in mouse were shown to have any discernible consequences . We have expressed HCD2 at high levels in transgenic mice and found a profound effect of the transgene on thymocyte differentiation. Transg enic thymuses are considerably reduced in cell number as a consequence of increased apoptosis of double-positive (DP) thymocytes in the cort ex. The remaining DP cells have up-regulated levels of T cell receptor (TCR) and are resistant to apoptosis mediated by administration of an tigen. These effects are dependent on the cytoplasmic domain of HCD2, as mice expressing comparable levels of a tailless HCD2 transgene have a normal phenotype. The HCD2 cytoplasmic domain contains several regi ons of identity with mouse CD2 and can interact efficiently with mouse intracellular signaling machinery. These results suggest then is cons iderable cross-talk between CD2 and TCR on developing thymocytes with consequences for the stimulation threshold of mature T cells.