Negative Selection to Minor H Determinants

It is well accepted that cytotoxic lymphocytes specific for viruses (1), haptens (2), and minor histocompatibility antigens (HA) 1 (3, 4) recognize antigen in an H-2restricted fashion during the effector phase. Precisely how the precursors of these cells respond to antigen during the induction phase, however, is poorly understood. In the case of skin graft rejection (5-9) and delayed-type hypersensitivity (10) to minor HA, mice can be primed with antigen presented on H-2-incompatible cells. Likewise, H-2 heterozygous mice primed with minor HA on cells of one parental strain develop cytolytic activity for target cells of both parental haplotyes (1 1, 12). This effect of cross-priming suggests either that certain aspects of the response to minor HA are not H-2 restricted or, conversely, that the antigens are processed by host cells and then presented in association with host H-2 determinants in a restricted fashion (12). To at tempt to clarify this question and, in particular, to gain information on the early stages of the cytotoxic T-cell response, we have studied the requirements for inducing negative and positive selection to minor HA in vivo. Previous work with this selection model has established that within 1 d of T-cell confrontation with such antigens as heterologous erythrocytes (13, 14) or foreign H-2 determinants (13-16) the responding T cells leave the circulation (undergo negative selection) and become selectively sequestered in the lymphoid tissues. Here, the cells proliferate extensively before reentering the circulation in expanded numbers after 2-3 d (positive selection). In the case ofT-helper cells for heterologous erythrocytes, T-cell selection appears not to involve a response to free antigen but rather to antigen that has been processed by macrophages or related cells (17). The present studies suggest that, at least in certain situations, a similar requirement for antigen processing applies to the induction of cytotoxic lymphocytes specific for minor HA.