Lombard-Vadnais Félix, Lacombe Julie, Chabot-Roy Geneviève, Ferron Mathieu, Lesage Sylvie
Immunologie-oncologie, Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, H1T 2M4, Canada.
Department of Microbiology & Immunology, McGill University, Montreal, QC, H3A 0G4, Canada.
Immunol Cell Biol. 2022 May;100(5):338-351. doi: 10.1111/imcb.12543. Epub 2022 Mar 30.
Pou2af1 encodes for OCA-B, a coactivator of OCT-1/2 transcription factors, which plays a key role in B-cell maturation. The function of OCA-B has also been studied in T cells, where T cells from Pou2af1 mice have impaired functions, such as cytokine production and T follicular helper (Tfh) differentiation. Arguably, some of these T-cell phenotypes may result from impaired T-B interactions, secondary to the well-documented B-cell defects in Pou2af1 mice. Yet, Pou2af1 is actively transcribed in activated T cells, suggesting a T-cell-intrinsic role. To isolate the T-cell-intrinsic impact of Pou2af1, we generated Pou2af1 mice with specific genetic disruption of Pou2af1 either in all hematopoietic cells or exclusively in T cells. While we confirm that Pou2af1 is expressed in activated T cells, we surprisingly find that T-cell cytokine production is not impaired in Pou2af1-deficient T cells. Moreover, Pou2af1-sufficient and Pou2af1-deficient T cells have comparable transcriptome profiles, arguing against a T-cell-intrinsic role for Pou2af1. In line with these observations, we demonstrate that Tfh maturation is influenced by T-cell-extrinsic deletion of Pou2af1, as observed both in competitive bone marrow chimeras and in Pou2af1 mice with specific deletion in B cells. Overall, this study provides strong evidence that Pou2af1 does not act as a transcriptional coactivator in T cells, and conclusively demonstrates that loss of OCA-B in B cells indirectly impacts Tfh differentiation, clarifying the role of OCA-B in the immune system.
Pou2af1编码OCA - B，它是OCT - 1/2转录因子的一种共激活因子，在B细胞成熟过程中起关键作用。OCA - B的功能也在T细胞中得到了研究，在Pou2af1基因敲除小鼠的T细胞中，其功能受损，如细胞因子产生和T滤泡辅助细胞（Tfh）分化。可以说，这些T细胞表型中的一些可能是由于Pou2af1基因敲除小鼠中B细胞缺陷导致的T - B相互作用受损所致。然而，Pou2af1在活化的T细胞中活跃转录，提示其在T细胞中有内在作用。为了分离Pou2af1在T细胞中的内在影响，我们构建了在所有造血细胞或仅在T细胞中特异性基因破坏Pou2af1的小鼠。虽然我们证实Pou2af1在活化的T细胞中表达，但我们惊讶地发现，Pou2af1缺陷的T细胞中T细胞细胞因子产生并未受损。此外，Pou2af1充足和Pou2af1缺陷的T细胞具有可比的转录组谱，这与Pou2af1在T细胞中的内在作用相矛盾。与这些观察结果一致，我们证明，在竞争性骨髓嵌合体和B细胞中特异性缺失Pou2af1的小鼠中均观察到，Tfh成熟受到Pou2af1细胞外缺失的影响。总体而言，本研究提供了强有力的证据表明Pou2af1在T细胞中不作为转录共激活因子，并最终证明B细胞中OCA - B的缺失间接影响Tfh分化，阐明了OCA - B在免疫系统中的作用。
