Essential Roles of the Transcription Factor NR4A1 in Regulatory T Cell Differentiation under the Influence of Immunosuppressants
Essential Roles of the Transcription Factor NR4A1 in Regulatory T Cell Differentiation under the Influence of Immunosuppressants
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DOI：
10.4049/jimmunol.2100808
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发表时间：
2022-04
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通讯作者：
T. Sekiya;H. Kasahara;Ryo Takemura;S. Fujita;J. Kato;N. Doki;Y. Katayama;Y. Ozawa;S. Takada;T. Eto;T. Fukuda;T. Ichinohe;M. Takanashi;M. Onizuka;Y. Atsuta;S. Okamoto;A. Yoshimura;S. Takaki;T. Mori
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作者：
T. Sekiya;H. Kasahara;Ryo Takemura;S. Fujita;J. Kato;N. Doki;Y. Katayama;Y. Ozawa;S. Takada;T. Eto;T. Fukuda;T. Ichinohe;M. Takanashi;M. Onizuka;Y. Atsuta;S. Okamoto;A. Yoshimura;S. Takaki;T. Mori
钙调神经磷酸酶抑制剂（CNIs），作为免疫抑制剂，具有革命性的移植医学对同种异体反应性T淋巴细胞的强烈抑制活性;然而，他们也可能会导致各种不良反应，包括感染和肾毒性的风险增加。调节性T（Treg）细胞可以用其有效的Ag特异性抑制活性补充CNI的有害副作用。然而，一些研究已经表明CNI抑制Treg细胞分化。因此，了解CNI抑制Treg细胞分化的机制以及在CNI存在下促进Treg细胞分化的方法具有重要的临床价值。在这篇文章中，我们报告，核孤儿受体Nr 4a 1在Treg细胞分化的CNIs的存在下起着关键作用。与其家族成员Nr 4a 2和Nr 4a 3不同，CNI处理不抑制Nr 4a 1的表达，从而在CNI存在下介导Treg细胞分化。在小鼠同种异体移植物抗宿主病模型中，Nr 4a 1通过促进给予环孢素A的小鼠中Treg细胞分化来介导耐受，延长受体的存活。此外，Nr 4a 1通过其激动剂的激活部分恢复了Treg细胞分化，这被环孢霉素A处理抑制。最后，我们发现，rs 2701129单核苷酸多态性，这被证明是下调NR 4A 1的表达，表现出一种趋势，在接受造血干细胞移植的患者慢性移植物抗宿主病的发病率较高。因此，我们的研究将具有临床意义，因为我们证明了在CNI存在下Nr 4a 1在Treg细胞分化中的作用。关键点Nr 4a 1在CNI存在下的Treg细胞分化中起着至关重要的作用。Nr 4a 1缺陷损害CNI存在下T细胞耐受性的诱导。
Calcineurin inhibitors (CNIs), used as immunosuppressants, have revolutionized transplantation medicine with their strong suppressive activity on alloreactive T lymphocytes; however, they may also cause various adverse effects, including an increased risk for infection and nephrotoxicity. Regulatory T (Treg) cells can complement the deleterious side effects of CNIs with their effective Ag-specific suppressive activities. However, several studies have shown that CNIs suppress Treg cell differentiation. Therefore, an understanding of the mechanisms by which CNIs suppress Treg cell differentiation, as well as an approach for promoting the differentiation of Treg cells in the presence of CNIs, has significant clinical value. In this article, we report that the nuclear orphan receptor Nr4a1 plays a pivotal role in Treg cell differentiation in the presence of CNIs. Unlike that of its family members, Nr4a2 and Nr4a3, the expression of Nr4a1 was not suppressed by CNI treatment, thereby mediating Treg cell differentiation in the presence of CNIs. In a mouse allogeneic graft-versus-host disease model, Nr4a1 mediated tolerance by promoting Treg cell differentiation in mice administered cyclosporine A, prolonging the survival of recipients. Furthermore, activation of Nr4a1 via its agonist partially restored Treg cell differentiation, which was suppressed by cyclosporine A treatment. Finally, we found that the rs2701129 single-nucleotide polymorphism, which was shown to downregulate NR4A1 expression, showed a trend toward a higher incidence of chronic graft-versus-host disease in patients undergoing hematopoietic stem cell transplantation. Therefore, our study will be of clinical significance because we demonstrated the role of Nr4a1 in Treg cell differentiation in the presence of CNIs. Key Points Nr4a1 plays crucial roles in Treg cell differentiation in the presence of CNIs. Nr4a1 deficiency impairs the induction of T cell tolerance in the presence of CNIs.