Disruption of the CD4-major histocompatibility complex class II interaction blocks the development of CD4(+) T cells in vivo.
The experiments presented in this report were designed to specifically examine the role of CD4-major histocompatibility complex (MHC) class II interactions during T cell development in vivo. We have generated transgenic mice expressing class II molecules that cannot interact with CD4 but that are otherwise competent to present peptides to the T cell receptor. MHC class II expression was reconstituted in Abeta gene knock-out mice by injection of a transgenic construct encoding either the wild-type I-Abetab protein or a construct encoding a mutation designed to specifically disrupt binding to the CD4 molecule. We demonstrate that the mutation, EA137 and VA142 in the beta2 domain of I-Ab, is sufficient to disrupt CD4-MHC class II interactions in vivo. Furthermore, we show that this interaction is critical for the efficient selection of a complete repertoire of mature CD4(+) T helper cells as evidenced by drastically reduced numbers of conventional CD4(+) T cells in animals expressing the EA137/VA142 mutant I-Ab and by the failure to positively select the transgenic AND T cell receptor on the mutated I-Ab. These results underscore the importance of the CD4-class II interaction in the development of mature peripheral CD4(+) T cells.
Riberdy
J M
JM
Department of Immunology, Box 3010, Duke University Medical Center, Durham, NC 27710, USA.
Mostaghel
E
E
Doyle
C
C
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology
D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell