Thymic development in human CD4 transgenic mice. Positive selection occurs after commitment to the CD8 lineage.
Developing T cells are positively selected on the basis of their recognition of polymorphic MHCs (major histocompatibility molecules). The CD4 and CD8 co-receptors, together with a compatible TCR-alpha beta, bind class II and class I MHC, respectively, delivering a signal that allows T cell maturation to proceed along the appropriate co-receptor lineage. During development, thymocytes first co-express CD4 and CD8 and subsequently commit to a single co-receptor phenotype. Debate exists over the stage at which positive selection occurs. Positive selection may precede or accompany co-receptor lineage commitment or occur subsequent to the acquisition of a single co-receptor phenotype. We developed transgenic (TG) mice expressing human CD4 (huCD4) on T cells. To study differentiation of CD8+ cells, huCD4 TG mice were bred with mice lacking class I MHC (class I-). This enabled us to assess maturation of mCD8+mCD4+huCD4+ thymocytes to mCD8+mCD4-huCD4+ cells after interaction between huCD4 and mclass II MHC. In the absence of huCD4, class I- mice failed to produce mCD8+ cells. However, expression of huCD4 allowed development of mCD8+mCD4-huCD4+ T cells, suggesting that selection of cells precommitted to the mCD8+mCD4- lineage occurred. Importantly, CD8+ T cells were increased in both the thymus and the periphery of huCD4 TG x class I- animals, indicating their intrathymic origin. V beta 14+ CD8+ T cells were also increased, as predicted for positive selection of CD8+ cells bearing class II-reactive TCRs. These data provide evidence that positive selection occurs at a late stage of thymocyte differentiation, after commitment to the CD8 lineage.
Paterson
R K
RK
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Burkly
L C
LC
Kurahara
D K
DK
Dunlap
A
A
Flavell
R A
RA
Finkel
T H
TH
D000818:Animals; D015704:CD4 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012641:Selection, Genetic; D013269:Stochastic Processes; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*
D015704:CD4 Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell