Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts

Simultaneous blockade of the CD40 and CD28 T cell costimulatory pathways ef fectively promotes skin allograft survival in C3H/HeJ mice, extending media n survival times (MSTs) beyond 100 days. This strategy is markedly less eff ective in C57BL/6 mice, with MSTs ranging between 20 and 30 days. In this s tudy, we investigate the underlying genetic causes of these distinct phenot ypes, Using H-2 congenic mice, we show that the genetic basis for the varie d responses between these two strains is independent of the H-2 locus and T cell precursor frequency. C57BL/6 mice treated with costimulation blockade are able to generate allospecific CTL- and IFN-gamma -producing T cells wi thin 3-4 wk posttransplant, whereas mice with a C3H background generate nei ther CTL- nor IFN-gamma -producing cells. Thus, differences appear to be in the generation of the immune response and not T cell homing. Strain differ ences in costimulation blockade-induced hyporesponsiveness persist in the a bsence of CD4(+) T cells, implying a direct effect on CD8(+) T cells. We de monstrate that genetic differences are important in cells of hemopoietic or igin and that the costimulation blockade-resistant phenotype is dominant. A nalysis of BXH recombinant inbred strains indicates that multiple loci cont ribute to the phenotype, and that the blockade resistance loci are prelimin arily linked to 17 markers on four chromosomes. We conclude that strain var iation in allograft MSTs following CD40/CD28 blockade results from the abil ity of CDS' T cells in some strains to use alternative modes of costimulati on to mount an effective alloresponse.