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 immature CD4⁺CD8⁺ thymocytes, with the fate of individual thymocytes determined by the specificity of T-cell antigen receptor they express. However, T-cell antigen receptor expression in immature CD4⁺CD8⁺ thymocytes is actively down-regulated in CD4⁺CD8⁺ thymocytes by CD4-mediated tyrosine kinase signals that are generated in the thymus as a result of CD4 engagement by intrathymic ligands. In the present study we have examined the effect of CD4 overexpression in CD4⁺CD8⁺ thymocytes on activation of CD4-associated p56^lck tyrosine kinase and regulation of T-cell antigen receptor expression. Augmented CD4 expression in CD4⁺CD8⁺ thymocytes did not result in commensurate increases in associated p56^lck molecules, so that CD4 expression was quantitatively disproportionate to that of its associated signaling molecule p56^lck. Interestingly, we found that CD4 overexpression significantly interfered with the ability of CD4 crosslinking to activate associated p56^lck molecules and significantly interfered with the ability of CD4 to regulate T-cell antigen receptor expression. Thus, this study provides an example in which receptor overexpression leads to decreased receptor signaling competence.