The fas antigen is involved in thymic T-cell development as a costimulatory molecule, but not in the deletion of neglected thymocytes.

Abstract

To determine whether the Fas antigen (Fas) is involved in thymic T-cell development, we introduced the lymphoproliferation (lpr) mutation into a T-cell receptor-alphabeta transgenic mouse (DO10 mouse) and generated 4 genotypes of T-cell receptor transgenic mice homozygous or heterozygous for the lpr mutation with selecting or nonselecting H-2 haplotype. Unexpectedly, we found that the homozygous Fas mutation (lpr/lpr) induced a marked reduction in CD4(+)CD8(+) double-positive (DP) thymocytes in mice with nonselecting background and that the thymus showed severe cortical atrophy. We also found that the homozygous Fas mutation inhibited the activation of DP thymocytes in the process of positive selection, as indicated by the lower levels of CD5 and CD69 expressions on DP thymocytes in lpr/lpr mice with both selecting and nonselecting background than those of lpr/+ mice. Furthermore, we found a significant skewing from CD4(+) to CD8(+) single-positive thymocytes in lpr/lpr mice with nonselecting background compared with that in the corresponding lpr/+ mice. Taken together, these results indicate that Fas is involved in thymic T-cell development, DP thymocyte generation and positive selection, as a costimulatory molecule but is not involved in the deletion of neglected thymocytes.