PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis.
PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis.
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PD-1阻断剂可调节皮肤利什曼病患者疲惫样T细胞的功能活动。
DOI：
10.3389/fimmu.2021.632667
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发表时间：
2021
影响因子：
7.3
通讯作者：
Gomes DCO
中科院分区：
文献类型：
--
作者：
Garcia de Moura R;Covre LP;Fantecelle CH;Gajardo VAT;Cunha CB;Stringari LL;Belew AT;Daniel CB;Zeidler SVV;Tadokoro CE;de Matos Guedes HL;Zanotti RL;Mosser D;Falqueto A;Akbar AN;Gomes DCO
感染巴西利什曼原虫的患者会出现衰弱的皮肤病变。抑制性检查点受体(ICR)在本病中诱导T细胞耗竭的作用尚不清楚。免疫组织学证实，患者皮损中包括PD-1、PDL-1、PDL-2、TIM-3和CTLA-4在内的ICR表达增加，其中CD4+和CD8+T细胞亚群中PD-1、TIM-3和CTLA-4的表达均增加。此外，与健康对照组相比，皮肤巨噬细胞表面的PDL-1/PDL-2配体增加。循环中表达T细胞的比例为PD1+，但不表达TIM-3或CTLA-4，与同一患者皮损中的比例呈正相关，提示PD-1可能同等地调节两个隔室的T细胞功能。在体外，阻断循环T细胞中PD-1信号可增强其增殖能力和干扰素-γ的产生，但不能促进其分泌肿瘤坏死因子-α。虽然我们以前发现循环中衰老的CD8+CD45RA+CD27-T细胞的积聚与皮损大小显著相关，但循环中T细胞上PD-1的表达程度与皮损的大小之间没有明显的相关性，这表明耗竭的类T细胞可能不参与皮肤的免疫病理。然而，我们在皮损和血液中都发现了疲惫的类T细胞。通过阻断PD-1靶向这一人群可能会改善T细胞功能，从而加速寄生虫的清除，从而减少皮肤利什曼病的皮肤病理。
Patients infected by Leishmania braziliensis develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4+ and CD8+ T cell subsets. Moreover, PDL-1/PDL-2 ligands were increased on skin macrophages compared to healthy controls. The proportions PD1+, but not TIM-3 or CTLA-4 expressing T cells in the circulation were positively correlated with those in the lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative capacity and IFN-γ production, but not TNF-α secretion in response to L. braziliensis recall antigen challenge in vitro. While we previously showed a significant correlation between the accumulation of senescent CD8+CD45RA+CD27- T cells in the circulation and skin lesion size in the patients, there was no such correlation between the extent of PD-1 expression by circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells may not contribute to the cutaneous immunopathology. Nevertheless, we identified exhausted-like T cells in both skin lesions and in the blood. Targeting this population by PD-1 blockade may improve T cell function and thus accelerate parasite clearance that would reduce the cutaneous pathology in cutaneous leishmaniasis.
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DOI：
10.4049/jimmunol.1301810
发表时间：
2013-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Esch KJ;Juelsgaard R;Martinez PA;Jones DE;Petersen CA
通讯作者：
Petersen CA
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
3.8
作者：
Hernández-Ruiz J;Salaiza-Suazo N;Carrada G;Escoto S;Ruiz-Remigio A;Rosenstein Y;Zentella A;Becker I
通讯作者：
Becker I
影响因子：
3.1
作者：
Cardoso, Thiago Marconi;Machado, Alvaro;Bacellar, Olivia
通讯作者：
Bacellar, Olivia
影响因子：
2.2
作者：
Faria, D. R.;Souza, P. E. A.;Dutra, W. O.
通讯作者：
Dutra, W. O.