Alterations in CD4 dependence accompany T cell development and differentiation.

Several studies have indicated that the necessity for co-receptor engagement during T cell activation depends on the avidity of the TCR-MHC interaction under investigation. Using thymocytes, naive T cells and a long-term T cell line isolated from 2B4 TCR transgenic mice, we have examined the role of the CD4 co-receptor on cells expressing the identical TCR at multiple stages of T cell maturation. When anti-CD4 Fab fragments were used to block CD4-MHC class II interactions, we found decreasing CD4 dependence as T cells matured. As a second approach to examining the role of the CD4 co-receptor, we generated I-Ek mutants defective in CD4 interactions. In the course of this study, we identified a new potential site for CD4 interaction in the beta1 domain of I-Ek. The new beta1 mutation and a mutation in the previously described CD4 binding site in the beta2 domain both interfere with stimulation of 2B4 thymocytes, but not mature T cells. Together these data demonstrate that the role of the CD4 co-receptor depends on the state of maturation of the T cell.