背景：B细胞淋巴瘤6（BCL6）是调节体液免疫反应的T激活辅助细胞（Tfh）细胞重要的转录因子，通过支持生发中心B细胞和浆细胞的成熟来调节体液免疫反应。本研究旨在调查T激活辅助细胞的扩展以及BCL6抑制剂FX1在急性和慢性心脏移植排异模型中的效果。方法：建立了急性和慢性心脏移植排异的小鼠模型。移植后的不同时间点收集脾细胞，通过流式细胞术检测CXCR5+PD-1+和CXCR5+BCL6+ Tfh细胞。随后，我们使用BCL6抑制剂FX1处理心脏移植物，并记录移植物的存活情况。对心脏移植物进行了苏木精-伊红、Elastica van Gieson和Masson染色以进行病理学分析。此外，还通过流式细胞术检测脾脏中CD4+ T细胞，效应器CD4+ T细胞（CD44+CD62L-），增殖性CD4+ T细胞（Ki67+）和Tfh细胞的比例和数量，以及与体液反应有关的细胞（浆细胞，生发中心B细胞，IgG1+ B细胞）和特异性供体抗体。结果：我们发现Tfh细胞在移植后的第14天显著增加。在急性心脏移植排异期间，即使BCL6抑制剂FX1没有延长心脏移植物的存活时间或减轻免疫反应，也能抑制Tfh细胞的扩张。在慢性心脏移植排异期间，FX1延长了心脏移植物的存活时间，并防止了心脏移植物中血管的闭塞和纤维化。FX1还减少了慢性排斥小鼠脾脏中CD4+ T细胞，效应器CD4+ T细胞，增殖性CD4+ T细胞和Tfh细胞的比例和数量。此外，FX1还抑制了脾脏中浆细胞，生发中心B细胞，IgG1+ B细胞和特异性供体抗体的比例和数量。结论：我们发现BCL6抑制剂FX1可以保护慢性心脏移植排异，并抑制Tfh细胞和体液免疫反应的扩张，这表明BCL6是治疗慢性心脏移植排异的潜在治疗靶点。Copyright © 2023 Xia, Jin and Wu.

Background: B cell lymphoma 6 (BCL6) is an important transcription factor of T follicular helper (Tfh) cells, which regulate the humoral response by supporting the maturation of germinal center B cells and plasma cells. The aim of this study is to investigate the expansion of T follicular helper cells and the effect of the BCL6 inhibitor FX1 in acute and chronic cardiac transplant rejection models. Methods: A mouse model of acute and chronic cardiac transplant rejection was established. Splenocytes were collected at different time points after transplantation for CXCR5+PD-1+ and CXCR5+BCL6+ Tfh cells detection by flow cytometry (FCM). Next, we treated the cardiac transplant with BCL6 inhibitor FX1 and the survival of grafts was recorded. The hematoxylin and eosin, Elastica van Gieson, and Masson staining of cardiac grafts was performed for the pathological analysis. Furthermore, the proportion and number of CD4+ T cells, effector CD4+ T cells (CD44+CD62L-), proliferating CD4+ T cells (Ki67+), and Tfh cells in the spleen were detected by FCM. The cells related to humoral response (plasma cells, germinal center B cells, IgG1+ B cells) and donor-specific antibody were also detected. Results: We found that the Tfh cells were significantly increased in the recipient mice on day 14 post transplantation. During the acute cardiac transplant rejection, even the BCL6 inhibitor FX1 did not prolong the survival or attenuate the immune response of cardiac graft, the expansion of Tfh cell expansion inhibit. During the chronic cardiac transplant rejection, FX1 prolonged survival of cardiac graft, and prevented occlusion and fibrosis of vascular in cardiac grafts. FX1 also decreased the proportion and number of splenic CD4+ T cells, effector CD4+ T cells, proliferating CD4+ T cells, and Tfh cells in mice with chronic rejection. Moreover, FX1 also inhibited the proportion and number of splenic plasma cells, germinal center B cells, IgG1+ B cells, and the donor-specific antibody in recipient mice. Conclusion: We found BCL6 inhibitor FX1 protects chronic cardiac transplant rejection and inhibits the expansion of Tfh cells and the humoral response, which suggest that BCL6 is a potential therapeutic target of the treatment for chronic cardiac transplant rejection.Copyright © 2023 Xia, Jin and Wu.