Based on CD25 expression, T follicular helper cells (Tfh) could be divided into T follicular regulatory (Tfr)-like subset (CD25⁺CD4⁺CXCR5⁺) and CD25⁻ Tfh subset (CD25⁻CD4⁺CXCR5⁺). Patients with diffuse large B cell lymphoma (DLBCL) display high level of Tfr-like cells in blood and tumor. This Tfr-like subset could suppress CD8 T cell response while promote tumor cell proliferation. In this study, we investigated the transcription factors and regulatory elements associated with Tfr-like cells in DLBCL patients. Both circulating and tumor-infiltrating Tfr-like cells presented slightly higher Blimp-1 expression and significantly higher Foxp3 expression than the CD25⁻ Tfh subset. As the IL-2 receptor, CD25 could be moderately upregulated in stimulated CD25⁻ Tfh cells. However, stimulated CD25⁻ Tfh cells could not upregulate Foxp3, indicating that the distinction between Foxp3-low CD25⁻CXCR5⁺CD4⁺ T cells and Foxp3-high CD25⁺CXCR5⁺CD4⁺ T cells was not due to differences in stimulation status. Regarding cytokine production, while both Tfr-like and CD25⁻ Tfh cells upregulated IL-21 and IL-10 during stimulation, the CD25⁻ Tfh cells presented significantly higher IL-21 and lower IL-10 expression than the Tfr-like cells, and the TGF-β expression was only increased in Tfr-like cells. Interestingly, IL-21 secreted from CD25⁻ Tfh cells negatively regulated the expression of Foxp3 and IL-10 of autologous Tfr-like cells. Together, these results demonstrated that the Tfr-like and CD25⁻ Tfh subsets of circulating Tfh cells presented different functions and should be investigated separately.

根据CD25的表达，T卵泡辅助细胞（Tfh）可分为T卵泡调节（Tfr）样亚群（CD25 ⁺ CD4 ⁺ CXCR5 ⁺）和CD25 ^- Tfh亚群（CD25 ^- CD4 ⁺ CXCR5 ⁺）。弥漫性大B细胞淋巴瘤（DLBCL）患者在血液和肿瘤中显示高水平的Tfr样细胞。这种类似Tfr的子集可以抑制CD8 T细胞反应，同时促进肿瘤细胞的增殖。在这项研究中，我们调查了DLBCL患者中与Tfr样细胞相关的转录因子和调控元件。与CD25 ^- Tfh亚群相比，循环的Tfr样细胞和肿瘤浸润的Tfr样细胞均表现出稍高的Blimp-1表达和Foxp3表达。作为IL-2受体，CD25在受刺激的CD25 ^- Tfh细胞中可能被适度上调。但是，刺激的CD25 ^- Tfh细胞不能上调Foxp3，表明Foxp3-low CD25 ^- CXCR5 ⁺之间的区别CD4 ⁺ T细胞和Foxp3高CD25 ⁺ CXCR5 ⁺ CD4 ⁺ T细胞不是由于刺激状态的差异。关于细胞因子的产生，虽然Tfr样和CD25 ^- Tfh细胞在刺激过程中均上调IL-21和IL-10，但CD25 ^- Tfh细胞比Tfr样细胞表现出更高的IL-21和更低的IL-10表达。 TGF-β表达仅在Tfr样细胞中增加。有趣的是，从CD25 ^- Tfh细胞分泌的IL-21会负面调节自体Tfr样细胞的Foxp3和IL-10的表达。总之，这些结果表明，总和生育率样和CD25 ^- 循环Tfh细胞的Tfh子集表现出不同的功能，应单独研究。