Antigen-specific T cell blasts may be separated from alloreactive cells on Percoll gradients. The absence of alloreactivity allowed us to study HLA-D/DR restriction of proliferative T cell responses towards PPD and HSV antigens using allogeneic antigen-presenting cells. An overriding impact of self HLA-D/DR determinants as restriction elements for in vivo sensitized T cells was demonstrated. Furthermore, evidence was obtained that the proliferative PPD response might be preferentially restricted by HLA-D/DR 1.