DISRUPTION OF THE CD4-MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II INTERACTION BLOCKS THE DEVELOPMENT OF CD4(-CELLS IN-VIVO() T)

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 t ransgenic mice expressing class II molecules that cannot interact with CD4 but that are otherwise competent to present peptides to the T cel l receptor. MHC class II expression was reconstituted in A beta gene k nock-out mice by injection of a transgenic construct encoding either t he wild-type I-A beta(b) protein or a construct encoding a mutation de signed to specifically disrupt binding to the CD4 molecule. We demonst rate that the mutation, EA137 and VA142 in the beta 2 domain of I-A(b) , is sufficient to disrupt CD4-MHC class II interactions in vivo. Furt hermore, we show that this interaction is critical for the efficient s election of a complete repertoire of mature CD4+ T helper cells as evi denced by drastically reduced numbers of conventional CD4+ T cells in animals expressing the EA137/VA142 mutant I-A(b) and by the failure to positively select the transgenic AND T cell receptor on the mutated I -A(.) These results underscore the importance of the CD4-class II inte raction in the development of mature peripheral CD4(+) T cells.