肿瘤相关 CD8(+)T 细胞耐受由红系祖细胞诱导

INTRODUCTION: CD8 + T cell tolerance plays an important role in tumor escape. Recent studies have shown that CD45 + erythroid progenitor cells (CD45 + EPCs) generated through splenic extramedullary erythropoiesis suppress tumor immunity. However, the mechanism underlying how CD45 + EPCs mediate CD8 + T cell tolerance remains incompletely understood and requires further research. METHODS: In this study, the antigen-processing abilities of CD45 + EPCs was verified through both in vitro and in vivo experiments. We have used the method of co-culture in vitro and adoptive transfer experiments in vivo to explore the effects of CD45 + EPCs on CD8 + T cell tolerance. RNA-sequencing analysis and blocking experiments were used to evaluate the role of ROS in the CD45 + EPC mediated tolerance of CD8 + T cells. Finally, we incorporated uric acid into the adoptive transfer experiments to rescue the CD45 + EPC mediated tumor-promoting effect. RESULTS AND DISCUSSION: We found that CD45 + EPCs take up soluble proteins, present antigenic epitopes on their surface, and induce antigen-specific CD8 + T cell anergy. In addition, we found that CD45 + EPC directly nitrates tyrosine within the TCR/CD8 complex via the production of reactive oxygen species and peroxynitrite, preventing CD8 + T cells from responding to their specific peptide antigens. Furthermore, uric acid treatment effectively abolished the immunosuppressive effects of CD45 + EPCs during CD8 + T cell adoptive transfer, thereby enhancing the anti-tumor efficacy. These results demonstrated that CD8 + T cell tolerance in tumor-bearing mice is induced by CD45 + EPCs. The results of this study have direct implications for tumor immunotherapy.