IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection.
IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection.
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DOI：
10.1016/j.healun.2021.06.008
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Gaber AO
中科院分区：
文献类型：
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作者：
Wang G;Zou D;Wang Y;Gonzalez NM;Yi SG;Li XC;Chen W;Gaber AO
B细胞通过产生供体特异性抗体和促进T细胞反应参与慢性移植排斥反应，但这些过程在转录水平上是如何调节的尚不清楚。在此，我们研究了转录因子干扰素调节因子4 （IRF4）在慢性移植排斥反应中控制B细胞反应的作用。我们培育了Irf4gfp报告小鼠，以测定IRF4在B细胞系中的表达。然后，我们使用B细胞特异性IRF4缺失的小鼠来确定NP-KLH免疫或同种异体心脏移植后IRF4在B细胞应答中的作用。特别是，移植后评估移植物存活和组织学，以及B和T细胞反应。IRF4在B细胞发育的不同阶段动态表达，而在生发中心（GC） B细胞中不存在。然而，IRF4消融在naïve和NP-KLH免疫小鼠的B细胞系中主要消除GC B细胞。在移植环境中，IRF4本质上在B细胞中起作用，并在多个水平上控制异体B细胞的反应，包括GC B细胞的产生、浆细胞分化、供体特异性抗体的产生和对T细胞反应的支持。B细胞特异性IRF4缺失联合瞬态CTLA4-Ig治疗可消除naïve受体小鼠的急性和慢性同种异体心脏移植排斥反应，但在供体皮肤致敏受体中则没有。B细胞需要IRF4介导慢性移植排斥反应。B细胞中IRF4的消融消除了异体B细胞的反应，也可能抑制了B细胞对异体T细胞的激活能力。靶向B细胞中的IRF4是消除慢性移植排斥反应的潜在治疗策略。
B cells contribute to chronic transplant rejection by producing donor-specific antibodies and promoting T cell response, but how these processes are regulated at the transcriptional level remains unclear. Herein, we investigate the role of transcription factor interferon regulatory factor 4 (IRF4) in controlling B cell response during chronic transplant rejection. We generated the Irf4gfp reporter mice to determine IRF4 expression in B cell lineage. We then used mice with B cell-specific IRF4 deletion to define the role of IRF4 in B cell response after NP-KLH immunization or allogeneic heart transplantation. In particular, graft survival and histology, as well as B and T cell responses, were evaluated after transplantation. IRF4 is dynamically expressed at different stages of B cell development and is absent in germinal center (GC) B cells. However, IRF4 ablation in the B cell lineage primarily eliminates GC B cells in both naïve and NP-KLH immunized mice. In the transplantation setting, IRF4 functions intrinsically in B cells and governs allogeneic B cell responses at multiple levels, including GC B cell generation, plasma cell differentiation, donor-specific antibody production, and support of T cell response. B cell-specific IRF4 deletion combined with transient CTLA4-Ig treatment abrogates acute and chronic cardiac allograft rejection in naïve recipient mice but not in donor skin-sensitized recipients. B cells require IRF4 to mediate chronic transplant rejection. IRF4 ablation in B cells abrogates allogeneic B cell responses and may also inhibit the ability of B cells to prime allogenic T cells. Targeting IRF4 in B cells represents a potential therapeutic strategy for eliminating chronic transplant rejection.
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影响因子：
32.4
作者：
Sciammas, Roger;Shaffer, A. L.;Singh, Harinder
通讯作者：
Singh, Harinder
影响因子：
30.8
作者：
Ye, BH;Cattoretti, G;DallaFavera, R
通讯作者：
DallaFavera, R
影响因子：
8.8
作者：
Zhang, Hedong;Wu, Jie;Chen, Wenhao
通讯作者：
Chen, Wenhao
亲和力成熟受到生发中心自然杀伤细胞抑制的损害。
影响因子：
8.8
作者：
Rydyznski CE;Cranert SA;Zhou JQ;Xu H;Kleinstein SH;Singh H;Waggoner SN
通讯作者：
Waggoner SN
DOI：
10.1038/nri3804
发表时间：
2015-03
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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