DECREASED SIGNALING COMPETENCE AS A RESULT OF RECEPTOR OVEREXPRESSION- OVEREXPRESSION OF CD4 REDUCES ITS ABILITY TO ACTIVATE P56(LCK) TYROSINE KINASE AND TO REGULATE T-CELL ANTIGEN RECEPTOR EXPRESSION IN IMMATURE CD4+CD8+ THYMOCYTES

Thymic selection of the developing T-cell repertoire occurs in immatur e CD4+CD8+ thymocytes, with the fate of individual thymocytes determin ed by the specificity of T-cell antigen receptor they express. However , T-cell antigen receptor expression in immature CD4+CD8+ thymocytes i s actively down-regulated in CD4+CD8+ thymocytes by CD4-mediated tyros ine kinase signals that are generated in the thymus as a result of CD4 engagement by intrathymic ligands. In the present study we have exami ned the effect of CD4 overexpression in CD4+CD8+ thymocytes on activat ion of CD4-associated p56lck tyrosine kinase and regulation of T-cell antigen receptor expression. Augmented CD4 expression in CD4+CD8+ thym ocytes did not result in commensurate increases in associated p56lck m olecules, so that CD4 expression was quantitatively disproportionate t o that of its associated signaling molecule p56lck. Interestingly, we found that CD4 overexpression significantly interfered with the abilit y of CD4 crosslinking to activate associated p56lck molecules and sign ificantly interfered with the ability of CD4 to regulate T-cell antige n receptor expression. Thus, this study provides an example in which r eceptor overexpression leads to decreased receptor signaling competenc e.