Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1.
Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1.
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WNT的激活通过表观遗传调节因子PRMT1促进记忆T细胞的多功能性。
DOI：
10.1172/jci140508
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发表时间：
2022-01-18
期刊：
影响因子：
--
通讯作者：
Chiu YL
中科院分区：
文献类型：
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作者：
Sung BY;Lin YH;Kong Q;Shah PD;Glick Bieler J;Palmer S;Weinhold KJ;Chang HR;Huang H;Avery RK;Schneck J;Chiu YL
T细胞多功能性是针对病原体和癌症的保护性免疫的标志，但控制它的分子机制仍然是难以捉摸的。我们发现，经典的Wnt激动剂抑制人记忆CD 8 + T细胞分化，同时促进高度多功能细胞的产生。Wnt激活的下游效应在去除药物后持续存在，并且T细胞在随后的细胞分裂后保持多功能，表明该效应是表观遗传调节的。Wnt激活诱导的基因表达模式富含干细胞特异性基因特征和蛋白质精氨酸甲基转移酶1（PRMT 1）（一种已知的表观遗传调节因子）的上调。PRMT 1 + CD 8 + T细胞与增强的多功能性相关，特别是产生IL-2的能力。相比之下，抑制PRMT 1可以改善Wnt对多功能性的影响。染色质免疫沉淀显示，H4 R3 me 2a，一个由PRMT 1介导的允许转录标记，在Wnt激活后IL-2启动子位点增加。在体内，Wnt处理的T细胞表现出上级的多功能性和持久性。当应用于巨细胞病毒（CMV）供体血清阳性，免疫血清阴性患者（D+/R-）肺移植患者样本时，Wnt激活增强CMV特异性T细胞多功能性，这在控制CMV疾病中很重要。这些发现揭示了控制T细胞多功能性的分子机制，并将PRMT 1确定为T细胞免疫治疗的潜在靶点。
T cell polyfunctionality is a hallmark of protective immunity against pathogens and cancer, yet the molecular mechanism governing it remains mostly elusive. We found that canonical Wnt agonists inhibited human memory CD8+ T cell differentiation while simultaneously promoting the generation of highly polyfunctional cells. Downstream effects of Wnt activation persisted after removal of the drug, and T cells remained polyfunctional following subsequent cell division, indicating the effect is epigenetically regulated. Wnt activation induced a gene expression pattern that is enriched with stem cell–specific gene signatures and upregulation of protein arginine methyltransferase 1 (PRMT1), a known epigenetic regulator. PRMT1+CD8+ T cells are associated with enhanced polyfunctionality, especially the ability to produce IL-2. In contrast, inhibition of PRMT1 ameliorated the effects of Wnt on polyfunctionality. Chromatin immunoprecipitation revealed that H4R3me2a, a permissive transcription marker mediated by PRMT1, increased at the IL-2 promoter loci following Wnt activation. In vivo, Wnt-treated T cells exhibited superior polyfunctionality and persistence. When applied to cytomegalovirus (CMV) donor–seropositive, recipient-seronegative patients (D+/R–) lung transplant patient samples, Wnt activation enhanced CMV-specific T cell polyfunctionality, which is important in controlling CMV diseases. These findings reveal a molecular mechanism governing T cell polyfunctionality and identify PRMT1 as a potential target for T cell immunotherapy.