美国拉霍亚免疫研究所Klaus Ley团队近期取得重要工作进展，他们研究提出，初始CD4⁺ T细胞上的PD-1和CD73协同限制对自身的反应。相关研究成果2024年11月21日在线发表于《自然—免疫学》上。

据介绍，用自身和外源肽接种疫苗分别诱导抗原特异性CD4⁺ T细胞的弱和强扩增，但其机制尚不清楚。

研究人员使用对整个小鼠主要组织相容性复合物II类多肽组的计算分析来测试胸腺中负选择对自身抗原特异的幼稚CD4⁺ T细胞库的影响程度，发现负选择仅部分解释了对自身和外来反应之间的差异。

在未感染和未接种疫苗的幼稚小鼠中，研究人员发现与外源特异性CD4⁺ T细胞相比，自身特异性CD4⁺ T细胞上程序性细胞死亡蛋白1（PD-1）和CD73 mRNA和蛋白的表达更高。PD-1和CD73的药理学或遗传阻断，显著增加了疫苗诱导的自身特异性CD4⁺T细胞的扩增，其转录组与外源特异性CD4⁺ T细胞的转录组相似，表明PD-1和CD73协同限制了CD4⁺ T细胞对自身的反应。

总之，这一研究结果对耐受性疫苗和癌症免疫疗法的开发具有启示意义。

附：英文原文

Title: PD-1 and CD73 on naive CD4+ T cells synergistically limit responses to self

Author: Nettersheim, Felix Sebastian, Brunel, Simon, Sinkovits, Robert S., Armstrong, Sujit Silas, Roy, Payel, Billitti, Monica, Kobiyama, Kouji, Alimadadi, Ahmad, Bombin, Sergei, Lu, Lihui, Zoccheddu, Martina, Oliaeimotlagh, Mohammad, Benedict, Chris A., Sette, Alessandro, Ley, Klaus

Issue&Volume: 2024-11-21

Abstract: Vaccination with self- and foreign peptides induces weak and strong expansion of antigen-specific CD4+ T cells, respectively, but the mechanism is not known. In the present study, we used computational analysis of the entire mouse major histocompatibility complex class II peptidome to test how much of the naive CD4+ T cell repertoire specific for self-antigens was shaped by negative selection in the thymus and found that negative selection only partially explained the difference between responses to self and foreign. In naive uninfected and unimmunized mice, we identified higher expression of programmed cell death protein 1 (PD-1) and CD73 mRNA and protein on self-specific CD4+ T cells compared with foreign-specific CD4+ T cells. Pharmacological or genetic blockade of PD-1 and CD73 significantly increased the vaccine-induced expansion of self-specific CD4+ T cells and their transcriptomes were similar to those of foreign-specific CD4+ T cells. We concluded that PD-1 and CD73 synergistically limited CD4+ T cell responses to self. These observations have implications for the development of tolerogenic vaccines and cancer immunotherapy.

DOI: 10.1038/s41590-024-02021-6

Source: https://www.nature.com/articles/s41590-024-02021-6