GITR activation ex vivo impairs CD8 T cell function in people with HIV on antiretroviral therapy.
GITR activation ex vivo impairs CD8 T cell function in people with HIV on antiretroviral therapy.
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DOI：
10.1016/j.isci.2023.108165
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发表时间：
2023-11-17
期刊：
影响因子：
5.8
通讯作者：
Lewin, Sharon R.
中科院分区：
文献类型：
--
作者：
Gubser, Celine;Pascoe, Rachel D.;Chang, Judy;Chiu, Chris;Solomon, Ajantha;Cao, Rosalyn;Rasmussen, Thomas A.;Lewin, Sharon R.
糖皮质激素诱导的肿瘤坏死因子相关蛋白（GITR）是一种共刺激免疫检查点分子，在调节性T细胞（Tconv）和活化的常规T细胞（Tconv）上组成性表达。在接受抑制性ART的PWH中采集的血液中，GITR表达在多种活化的CD 4和CD 8 T细胞亚群中减少，但在T细胞亚群中增加。与总CD 8 T细胞相比，HIV特异性CD 8 T细胞表达更高水平的GITR和程序性细胞死亡蛋白1（PD-1）。在用HIV肽和GITR-配体（L）刺激后，我们证明了HIV特异性CD 8 T细胞的杀伤显著降低，并且耗竭概况增加。T细胞受体与GITR-L共刺激消除了Treg抑制并诱导了CD 4 Tconv的扩增。我们的结论是，GITR激活是一个额外的因素，导致艾滋病毒免疫反应受损的PWH ART和GITR激动剂抗体不应该追求的艾滋病毒治愈策略。与总CD 8 T细胞相比，HIV特异性CD 8 T细胞表达更高水平的GITR GITR刺激降低细胞毒性并进一步耗尽HIV特异性CD 8 T细胞GITR刺激消除Treg抑制并增加CD 4 T细胞增殖GITR刺激增强HIV患者受损的HIV特异性免疫应答免疫学;细胞生物学
Glucocorticoid-induced tumor necrosis factor related protein (GITR) is a co-stimulatory immune checkpoint molecule constitutively expressed on regulatory T cells (Tregs) and on activated T conventional cells (Tconv). In blood collected from PWH on suppressive ART, GITR expression was reduced in multiple activated CD4 and CD8 T cell subsets but was increased in Tregs. HIV specific CD8 T cells expressed higher levels of GITR and programmed cell death protein 1 (PD-1) compared to total CD8 T cells. Following stimulation with HIV peptides and GITR-ligand (L), we demonstrated a significant decrease in killing by HIV specific CD8 T cells and an increased exhausted profile. T cell receptor co-stimulation with GITR-L abrogated Treg suppression and induced expansion of CD4 Tconv. We conclude that GITR activation is an additional factor contributing to an impaired HIV immune response in PWH on ART and that GITR agonist antibodies should not be pursued for HIV cure strategies. HIV-specific CD8 T cells expressed higher levels of GITR compared to total CD8 T cells GITR stimulation decreased cytotoxicity and further exhausted HIV specific CD8 T cells GITR stimulation abrogated Treg suppression and increased CD4 T cell proliferation GITR stimulation enhanced impaired HIV-specific immune responses in people with HIV Immunology; Cell biology
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影响因子：
5.4
作者：
Kober, Johanna;Leitner, Judith;Klauser, Christoph;Woitek, Ramona;Majdic, Otto;Stoeckl, Johannes;Herndler-Brandstetter, Dietmar;Grubeck-Loebenstein, Beatrix;Reipert, Birgit M.;Pickl, Winfried F.;Pfistershammer, Katharina;Steinberger, Peter
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影响因子：
4.4
作者：
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通讯作者：
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影响因子：
11.1
作者：
Gubser C;Chiu C;Lewin SR;Rasmussen TA
通讯作者：
Rasmussen TA
影响因子：
20.3
作者：
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通讯作者：
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