Genetic Characterization of Strain Differences in the Ability to Mediate CD40/CD28-Independent Rejection of Skin Allografts

Abstract

Simultaneous blockade of the CD40 and CD28 T cell costimulatory pathways effectively promotes skin allograft survival in C3H/HeJ mice, extending median survival times (MSTs) beyond 100 days. This strategy is markedly less effective in C57BL/6 mice, with MSTs ranging between 20 and 30 days. In this study, we investigate the underlying genetic causes of these distinct phenotypes. Using H-2 congenic mice, we show that the genetic basis for the varied 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-γ-producing T cells within 3–4 wk posttransplant, whereas mice with a C3H background generate neither CTL- nor IFN-γ-producing cells. Thus, differences appear to be in the generation of the immune response and not T cell homing. Strain differences in costimulation blockade-induced hyporesponsiveness persist in the absence of CD4+ T cells, implying a direct effect on CD8+ T cells. We demonstrate that genetic differences are important in cells of hemopoietic origin and that the costimulation blockade-resistant phenotype is dominant. Analysis of BXH recombinant inbred strains indicates that multiple loci contribute to the phenotype, and that the blockade resistance loci are preliminarily linked to 17 markers on four chromosomes. We conclude that strain variation in allograft MSTs following CD40/CD28 blockade results from the ability of CD8+ T cells in some strains to use alternative modes of costimulation to mount an effective alloresponse.

Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

“…The resistance to the effects of costimulatory blockade was alloantigen specific in that B10.A DST/aCD40L was highly effective in the presence of T cells primed to an entirely separate set of alloantigens (Table 1). Our studies confirm previously published findings that naïve CD8 π T cells (28)(29)(30)(31), T cells primed to viral antigens (32,33), and in some cases CD4 π T cells (21,34) can be resistant to the effects of costimulatory blockade. DST/aCD40L fully prevented the expansion and activation of the alloreactive T cells in naïve animals transplanted with B10.A hearts (associated with prolonged graft survival, Figure 2).…”

Activation of Alloreactive CD8+ T Cells Operates Via CD4-Dependent and CD4-Independent Mechanisms and Is CD154 Blockade Sensitive

“…Similarly, alloreactive TCR-transgenic CD8 ϩ T cells transferred into CBA hosts became activated, proliferated, and migrated to B10 cardiac allografts despite the CD154 blockade (14). Distinct recipient strains and transplant models might potentially contribute to the differential effects of CD154 blockade (24). We believe that the rejection mechanism involving different aspects of T cell function might be the key.…”

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

“…While initially promising, with more extensive tests of this approach the success has been somewhat limited, particularly when translated to larger animal models and to the clinic [1]. In hindsight this may not be surprising given that tolerance naturally occurs primarily in the thymus and only secondarily in the periphery [2].…”