Fas modulates both positive and negative selection of thymocytes.
We studied the functional role of Fas (CD95) in thymic T cell development using the TCR transgenic mice homozygous for the lpr mutation, DO10 lpr/lpr mice. In DO10 lpr/lpr mice, the differentiation of CD4(+)CD8(+) double-positive (DP) thymocytes to CD4(+) single-positive (SP) thymocytes was markedly impaired, as indicated by decreased generation of CD4(+) SP thymocytes and reduced ratio of CD4(+) SP thymocytes to DP thymocytes in lpr/lpr mice compared with those of +/+ mice. Activation of DP thymocytes in the process of positive selection was also significantly inhibited in DO10 lpr/lpr mice, as shown by the lower levels of CD69 expression on DP thymocytes in lpr/lpr mice compared to +/+ mice. Furthermore, the deletion of DP thymocytes induced by in vivo administration of OVA peptide (up to 150 micrograms) and anti-TCR clonotype mAb did not occur in DO10 lpr/lpr mice, whereas these treatments significantly decreased DP thymocytes in DO10 +/+ mice. On the other hand, no significant difference in DO10 transgenic TCR expression on DP thymocytes was found between DO10 lpr/lpr and +/+ mice. Together, these results indicate that Fas is importantly involved in both positive and negative selection of thymocytes.
Kurasawa
K
K
Department of Internal Medicine II, Chiba University School of Medicine, Chiba, 260, Japan.
Hashimoto
Y
Y
Iwamoto
I
I
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002455:Cell Division; D019891:Leukopoiesis; D008221:Lymphoid Tissue / Q000166:cytology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology; D019014:fas Receptor / Q000502:physiology*
D000911:Antibodies, Monoclonal; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019014:fas Receptor