INDUCTION OF ANTI-ALLO-CLASS-I H-2 TOLERANCE BY INACTIVATION OF CD8+ HELPER T-CELLS, AND REVERSAL OF TOLERANCE THROUGH INTRODUCTION OF 3RD-PARTY HELPER T-CELLS

The intravenous sensitization of C57BL/6 (B6) mice with class I H-2-disparate B6-C-H-2bm1 (bml) spleen cells resulted in the abrogation of CD8+ T cell-mediated anti-bml (proliferative and interleukin 2-producing) T helper (Th) cell activities. In vitro stimulation of lymphoid cells from these mice with bml cells, however, generated a reduced, but appreciable, anti-bml cytotoxic T lymphocyte (CTL) response. Moreover, the anti-bml CTL response, upon stimulation with [bml x B6-C-H-26-12 (bm12)]F1 spleen cells, was enhanced when compared with the response induced upon stimulation with bml cells. These in vitro results were reflected on in vivo graft rejection responses; bml skin grafts engrafted in the bml-presensitized B6 mice exhibited prolonged survival, whereas (bml x bm12)F1 grafts placed collateral to bml grafts (dual engrafted mice) inhibited the tolerance to bml. In the B6 mice 1-2 d after rejecting the bml grafts, anti-bml Th activities remained marginal, whereas potent anti-bml CTL responses were found to be generated from their spleen cells. Administration in vivo of anti-CD4 antibody into bml-presensitized, dual graft-engrafted mice prolonged bml graft survival and interfered with enhanced induction of anti-bml CTL activity. These results indicate that anti-class I alloantigen (bml) tolerance as induced by intravenous presensitization with the relevant antigens is not ascribed to the elimination of CD8+ CTL precursors, but to the specific inactivation of CD8+ Th cells, whose function can be bypassed by activating third-party Th cells. © 1990, Rockefeller University Press., All rights reserved.