美国斯坦福大学Mark M. Davis团队揭示人类CD4⁺和CD8⁺调节性T细胞在控制自身反应性免疫反应中的不同作用。这一研究成果于2025年1月13日在线发表在国际学术期刊《自然—免疫学》上。

研究人员分析了表达叉头框蛋白P3（FOXP3）的CD4⁺调节性T细胞，和表达杀伤细胞免疫球蛋白样受体的CD8⁺调节性T细胞，在控制人类扁桃体来源的免疫类器官中，自身反应性T和B淋巴细胞中的相对贡献。FOXP3和GZMB分别编码FOXP3和颗粒酶B蛋白，这两种蛋白对CD4⁺和CD8⁺调节性T细胞的抑制功能至关重要。

利用CRISPR-Cas9基因编辑技术，研究人员成功将这些基因的表达减少了约90–95%。在扁桃体T细胞中敲除FOXP3导致对多种自身抗原的抗体产生，并增加了针对流感的高亲和力抗体的生成。相比之下，敲除GZMB导致滤泡辅助性T细胞的数量增加，这与小鼠模型中观察到的CD8⁺调节性T细胞的消失一致，并显著扩增了自身反应性CD8⁺和CD4⁺ T细胞。

这些发现突出了CD8⁺和CD4⁺调节性T细胞，在调控细胞和体液免疫反应，以预防自身免疫中的不同但互补的作用。

附：英文原文

Title: Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses

Author: Chen, Xin, Ghanizada, Mustafa, Mallajosyula, Vamsee, Sola, Elsa, Capasso, Robson, Kathuria, Karan Raj, Davis, Mark M.

Issue&Volume: 2025-01-13

Abstract: Here we analyzed the relative contributions of CD4+ regulatory T cells expressing Forkhead box protein P3 (FOXP3) and CD8+ regulatory T cells expressing killer cell immunoglobulin-like receptors to the control of autoreactive T and B lymphocytes in human tonsil-derived immune organoids. FOXP3 and GZMB respectively encode proteins FOXP3 and granzyme B, which are critical to the suppressive functions of CD4+ and CD8+ regulatory T cells. Using CRISPR–Cas9 gene editing, we were able to achieve a reduction of ~90–95% in the expression of these genes. FOXP3 knockout in tonsil T cells led to production of antibodies against a variety of autoantigens and increased the affinity of influenza-specific antibodies. By contrast, GZMB knockout resulted in an increase in follicular helper T cells, consistent with the ablation of CD8+ regulatory T cells observed in mouse models, and a marked expansion of autoreactive CD8+ and CD4+ T cells. These findings highlight the distinct yet complementary roles of CD8+ and CD4+ regulatory T cells in regulating cellular and humoral responses to prevent autoimmunity.

DOI: 10.1038/s41590-024-02062-x

Source: https://www.nature.com/articles/s41590-024-02062-x