■CD8+T细胞耐受在肿瘤逃逸中起重要作用。最近的研究表明,通过脾脏髓外红细胞生成产生的CD45红系祖细胞(CD45EPCs)可抑制肿瘤免疫。然而,CD45+EPCs介导CD8+T细胞耐受的潜在机制尚不完全清楚,需要进一步研究.
■在这项研究中,通过体外和体内实验验证了CD45EPCs的抗原加工能力。我们采用体外共培养和体内过继转移实验的方法,探讨了CD45+EPCs对CD8+T细胞耐受性的影响。RNA测序分析和阻断实验用于评估ROS在⑶45+EPC介导的CD8+T细胞耐受性中的作用。最后,我们将尿酸纳入过继转移实验,以挽救CD45+EPC介导的促肿瘤作用.
■我们发现CD45+EPCs吸收可溶性蛋白质,在它们的表面上呈现抗原表位,并诱导抗原特异性CD8+T细胞无反应性。此外,我们发现,CD45+EPC通过产生活性氧和过氧亚硝酸盐直接在TCR/CD8复合物中硝酸酪氨酸,阻止CD8+T细胞对其特异性肽抗原作出反应。此外,尿酸治疗有效地消除了CD8+T细胞过继转移过程中CD45+EPCs的免疫抑制作用,从而增强抗肿瘤功效。这些结果表明,CD45EPCs可诱导荷瘤小鼠的CD8T细胞耐受性。这项研究的结果对肿瘤免疫治疗具有直接意义。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.