Results Haplotype - specific Suppression of CTL Response to Minor H Antigens

Minor histocompatibility (H) 1 antigens are non-H-2 transplantation antigens, of which ~40 have been identified (1). A vigorous cytotoxic T lymphocyte (CTL) response to minor H antigens requires in vivo priming, and CTL so generated are H2 restricted in their activity (2, 3). Priming for minor H antigens generally involves injection of ~107 viable spleen cells. Induction of CTL by in vivo priming with lymphoid cells appears to follow several pathways, some of which are diagrammed schematically in Fig. 1. We have previously shown that some component of the antigen-bearing spleen cell population is competent to present minor H antigens to CTL precursors directly (4). Recipient cells also appear capable of presenting injected minor H antigens, as evidenced by the phenomenon of cross-priming, which refers to the finding that (A × B)F1 mice injected with H-2 A minor-H-different spleen cells (A') will generate not only H-2 Abut also H-2B-restricted CTL activity (5). In our view, the most experimentally sound explanation for cross-priming is that antigenpresenting cells in an (A × B)F1 animal injected with A' spleen cells can reprocess and present these minor H antigens in conjunction with both H-2 A and H-2 B (4, 6, 7). Consistent with that view, it seemed likely that a kinetic study of F1 mice injected with A' cells would reveal early direct priming to minor H plus-H-2 A followed later, after antigen reprocessing, by cross-priming to minor H-plus-H-2 B. To our surprise, 3-6 d after antigen injection the minor H-specifc, H-2A-restricted CTL response in such animals is severely depressed relative to the minor H-plus-H-2 B and third-party alloreactive responses. Experiments described below were designed to investigate the nature of this haplotype-specific CTL hyporeactivity.