In previous studies we have shown that the response of T cells to antigen presented by epidermal Langerhans cells (LC) is restricted by products of the HLA-D region. An optimal antigen-specific response required that the LC used for antigen presentation shared both, or at least one, of the D/DR determinants of the T-cell donor. These studies were, however, disturbed by a strong allogeneic response induced by the foreign D/DR determinants of the LC. We report here that by separating the antigen-specific T cells from those that are alloreactive, a clearer picture of the D/DR restriction phenomenon may be obtained. Furthermore, the present studies demonstrate that the same D/DR determinants function as restriction elements on peripheral blood monocytes and LC.