Fas modulates both positive and negative selection of thymocytes

We studied the functional role of Fas (CD95) in thymic T cell development u sing the TCR transgenic mice homozygous for the 1pr mutation, DO10 1pr/1pr mice. In DO10 1pr/1pr mice, the differentiation of CD4(+)CD8(+) double-posi tive (DP) thymocytes to CD4(+) single-positive (SP) thymocytes was markedly impaired, as indicated by decreased generation of CD4+ SP thymocytes and r educed ratio of CD4+ SP thymocytes to DP thymocytes in 1pr/1pr mice compare d with those of +/+ mice. activation of DP thymocytes in the process of pos itive selection was also significantly inhibited in DO10 1pr/Ipr mice, as s hown by the lower levels of CD69 expression on DP thymocytes in 1pr/1pr mic e compared to +/+ mice. Furthermore, the deletion of DP thymocytes induced by in vivo administration of OVA peptide (up to 150 mu g) and anti-TCR clon otype mAb did not occur in DO10 1pr/1pr mice, whereas these treatments sign ificantly decreased DP thymocytes in DO10 +/+ mice. On the other hand, no s ignificant difference in DO10 transgenic TCR expression on DP thymocytes wa s found between DO10 1pr/1pr and +/+ mice. Together, these results indicate that Fas is importantly involved in both positive and negative selection o f thymocytes. (C) 1999 Academic Press.