The cytoplasmic domain of CD8β regulates Lck kinase activation and CD8 T cell development

Previous studies have shown that CD8β plays a role in both enhancing CD8α-associated Lck kinase activity and promoting the development of CD8- lineage T cells. To examine the role of this enhancement in the maturation of CD8-lineage cells, we assessed CD8α-associated Lck kinase activity in both T cell hybridomas and thymocytes of mice expressing CD8β mutations known to impair CD8 T cell development. Lack of CD8β expression or expression of a cytoplasmic domain-deleted CD8β resulted in a severalfold reduction in CD8α-associated Lck kinase activity compared with that observed with cells expressing wild-type CD8β chain. This analysis indicated a critical role for the cytoplasmic domain of CD8β in the regulation of CD8α-associated Lck activity. Decreased CD8α-associated Lck activity observed with the various CD8β mutations also correlated with diminished in vivo cellular tyrosine phosphorylation. In addition, analysis of CD8β mutant mice (CD8β^-/^- or cytoplasmic domain-deleted CD8β transgenic) indicated that the degree of reduction in CD8α-associated Lck activity associated with each mutation correlated with the severity of developmental impairment. These results support the importance of CD8b-mediated enhancement of CD8α-associated Lck kinase activity in the differentiation of CD8 single-positive thymocytes.