CYTOTOXIC T-LYMPHOCYTE ANTIGEN-4 IS INDUCED IN THE THYMUS UPON IN-VIVO ACTIVATION AND ITS BLOCKADE PREVENTS ANTI-CD3-MEDIATED DEPLETION OF THYMOCYTES

The development of a normal T cell repertoire in the thymus is depende nt on the interplay between signals mediating cell survival (positive selection) and cell death (negative selection or death by neglect). Al though the CD28 costimulatory molecule has been implicated in this pro cess, it has been difficult to establish a role for the other major co stimulatory molecule, cytotoxic T lymphocyte antigen (CTLA)-4. Here we report that in vivo stimulation through the T cell receptor (TCR)-CD3 complex induces expression of CTLA-4 in thymocytes and leads to the a ssociation of CTLA-4 with the SH2 domain-containing phosphatase (SHP)- 2 tyrosine phosphatase. Moreover, intrathymic CTLA-4 blockade dramatic ally inhibits anti-CD3-mediated depletion of CD4(+)CD8(+) double posit ive immature thymocytes. Similarly, anti-CD3-mediated depletion of CD4 (+)CD8(+) double positive cells in fetal thymic organ cultures could a lso be inhibited by anti-CTLA-4 antibodies. Thus, our data provide evi dence for a role of CTLA-4 in thymic selection and suggest a novel mec hanism contributing to the regulation of TCR-mediated selection of T c ell repertoires.