Effects of Anti-PD-L1 or IL-15/IL-15Rα-Fc Complex Treatment on CD4-independent CD8+ T Cell-Mediated Skin Allograft Rejection 3401

Description Purpose CD8+ T cells, without CD4+ T cell help, independently reject skin but not other allografts for unknown reasons. This study determined the effects of T cell exhaustion and anergy on graft-infiltrating CD8+ T cells in CD4-depleted skin transplant recipients. Methods C57BL/6J mice were transplanted with MHC-mismatched skin allografts, depleted of CD4+ T cells, and treated with anti-PD-L1 or IL-15/IL-15Rα-Fc complex. Skin allografts were harvested at the time of rejection and analyzed by flow cytometry. Results Alloprimed effector CD8+ T cells comprised up to 40% of graft-infiltrating cells in CD4-deficient conditions. Treatment with either anti-PD-L1 or IL-15/IL-15Rα-Fc complex enhanced the proportion of graft-infiltrating CD62LloCD44hi CD8+T cells (78% vs 51%; p < 0.03 and 68% vs 51%; p < 0.05, respectively). The majority of graft-infiltrating CD8+ T cells expressed TNFα or granzyme B and treatment with anti-PD-L1, but not IL-15/IL-15Rα-Fc complex, enhanced the proportion of TNFα+ graft-infiltrating CD8+ T cells (42% vs 32%; p < 0.05). IL-15/IL-15Rα-Fc complex and anti-PD-L1 treatment reduced the expression of exhaustion markers Tim-3 (18% vs 30%; p < 0.004) and LAG-3 (19% vs 34%; p < 0.02), respectively, but neither treatment accelerated skin allograft rejection. Conclusions Although the aforementioned treatments enhance the proportion of non-exhausted effector CD4-independent CD8+T cells in skin allografts, these treatments did not accelerate skin rejection kinetics. Funding Sources Acknowledgements: Steven Elzein, MD is a Burroughs Wellcome Fund Fellow supported by a Burroughs Wellcome Fund Physician Scientist Institutional Award to the Texas A&M University Academy of Physician Scientists.