Belatacept was developed to replace calcineurin inhibitors in kidney transplantation. Its use is associated with better kidney transplant function, a lower incidence of anti-donor antibodies and higher graft survival. However, it is also associated with a higher risk of cellular rejection. We studied the activation and proliferation mechanisms of belatacept-resistant T lymphocytes (TLs), to identify new pathways for control. We performed a transcriptomic analysis on CD4⁺CD57⁺PD1⁻ memory TLs, which are responsible for a higher incidence of graft rejection, after allogeneic stimulation with activated dendritic cells (aDCs) in the presence or absence of belatacept. After six hours of contact with aDCs, the (CD4⁺CD57⁺PD1⁻) (CD4⁺CD57⁺PD1⁺) and (CD4⁺CD57⁻) lymphocytes had different transcriptional profiles with or without belatacept. In the CD4⁺CD57⁺PD1⁻population, the IFNα-dependent activation pathway was positively overrepresented, and IRF7 transcript levels were high. IRF7 was associated with IFNα/β and IL-6 regulation. The inhibition of both these cytokines in a context of belatacept treatment inhibited the proliferation of CD4⁺CD57⁺PD1⁻ T cells. Our results show that IRF7 is rapidly upregulated in belatacept-resistant CD4⁺CD57⁺PD1⁻ TLs. The inhibition of type I IFN or IL-6 in association with belatacept treatment reduces the proliferation of belatacept-resistant TLs, paving the way for new treatments for use in organ transplantation.

中文翻译：

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belatacept 抗性 T 细胞的增殖需要早期 IFNα 通路激活

Belatacept 被开发用于替代肾移植中的神经钙蛋白抑制剂。它的使用与更好的肾移植功能、更低的抗供体抗体发生率和更高的移植存活率有关。然而，它也与较高的细胞排斥风险有关。我们研究了 belatacept 抗性 T 淋巴细胞 (TL) 的激活和增殖机制，以确定新的控制途径。我们对 CD4 ⁺ CD57 ⁺ PD1 ^-记忆 TL 进行了转录组学分析，在存在或不存在 belatacept 的情况下，在用活化的树突细胞 (aDC) 进行同种异体刺激后，这些 TL 导致更高的移植物排斥发生率。与 aDCs 接触六个小时后，(CD4 ⁺ CD57 ⁺PD1 ^- ) (CD4 ⁺ CD57 ⁺ PD1 ⁺ ) 和 (CD4 ⁺ CD57 ^- ) 淋巴细胞在有或没有贝拉西普的情况下具有不同的转录谱。在 CD4 ⁺ CD57 ⁺ PD1 ⁻群体中，IFNα 依赖性激活途径呈阳性，并且 IRF7 转录物水平很高。IRF7 与 IFNα/β 和 IL-6 调节相关。在 belatacept 治疗的背景下抑制这两种细胞因子会抑制 CD4 ⁺ CD57 ⁺ PD1 ^- T 细胞的增殖。我们的结果表明 IRF7 在 belatacept 抗性 CD4 ^{+中迅速上调}CD57 ⁺ PD1 ^- TL。与 belatacept 治疗相关的 I 型 IFN 或 IL-6 的抑制减少了 belatacept 抗性 TL 的增殖，为用于器官移植的新疗法铺平了道路。