CD8 cells of patients with diffuse cutaneous leishmaniasis display functional exhaustion: the latter is reversed, in vitro, by TLR2 agonists.
CD8 cells of patients with diffuse cutaneous leishmaniasis display functional exhaustion: the latter is reversed, in vitro, by TLR2 agonists.
复制标题
DOI：
10.1371/journal.pntd.0000871
复制
发表时间：
2010-11-02
影响因子：
3.8
通讯作者：
Becker I
中科院分区：
文献类型：
--
作者：
Hernández-Ruiz J;Salaiza-Suazo N;Carrada G;Escoto S;Ruiz-Remigio A;Rosenstein Y;Zentella A;Becker I
墨西哥利什曼原虫（Lm）引起局部（LCL）和弥漫性（DCL）皮肤利什曼病。DCL患者的细胞免疫反应较差，导致慢性化。已经提出，CD 8 T淋巴细胞（CD 8）在感染清除中起着至关重要的作用，尽管CD 8细胞毒性在疾病控制中的作用尚未阐明。与LCL患者相比，DCL患者的病变显示具有较低数量的CD 8，利什曼杀剂治疗可恢复CD 8数量。CD 8对利什曼原虫的显著反应使我们分析了LCL和DCL患者CD 8之间可能的功能差异。我们比较了从PBMC中纯化的CD 8对感染墨西哥利什曼原虫（MOi）的自体巨噬细胞（MO）的IFNγ产生、抗原特异性增殖和细胞毒性。此外，我们分析了两组患者的组织活检，以寻找与病变中凋亡细胞相关的细胞毒性证据。我们发现，与LCL患者相比，DCL患者的CD 8细胞在MOi刺激下表现出低细胞毒性、低抗原特异性增殖和低IFNγ产生。此外，DCL患者在其病变中的TUNEL+细胞显著较少。这些特征类似于慢性感染中描述的细胞“衰竭”。我们打算通过将DCL患者的CD 8细胞与TLR 2激动剂：Lm脂磷酸聚糖（LPG）或Pam 3Cys预孵育来恢复其功能能力。两种刺激均恢复了针对MOi的细胞毒性、抗原特异性增殖和IFNγ产生，而PD-1（一种与细胞耗竭相关的分子）表达降低。我们的工作表明，CD 8应答与LCL患者Lm感染的控制有关，而DCL患者的慢性感染导致CD 8功能衰竭，这可能有助于疾病传播。这是第一份报告，显示功能耗尽的CD 8 T淋巴细胞在DCL患者的存在，此外，与TLR 2配体的预刺激可以恢复DCL患者的CD 8 T淋巴细胞对墨西哥利什曼原虫感染的巨噬细胞的效应机制。 墨西哥利什曼原虫引起局部和弥漫性皮肤利什曼病。前者是一种良性疾病，而弥漫性皮肤利什曼病是一种慢性毁容疾病，目前尚无治愈方法，这些患者的免疫细胞对寄生虫的反应很差。已经提出，通过CD 8 T细胞消除利什曼原虫感染的细胞对于疾病控制至关重要。我们比较了局部和弥漫性皮肤利什曼病患者的CD 8 T细胞的功能特征。我们发现，与良性疾病患者相比，弥漫性皮肤利什曼病患者的CD 8 T细胞功能衰竭。我们能够通过与刺激TLR 2的分子一起培养这些细胞来恢复它们的功能能力。这是第一份报告表明，刺激TLR 2可以恢复效应机制的功能耗尽的CD 8细胞从弥漫性皮肤利什曼病患者。这一发现将有助于为感染寄生虫墨西哥利什曼原虫的患者设计新的治疗方案，这些患者患有进行性，不可治愈的弥漫性皮肤利什曼病。
Leishmania mexicana (Lm) causes localized (LCL) and diffuse (DCL) cutaneous leishmaniasis. DCL patients have a poor cellular immune response leading to chronicity. It has been proposed that CD8 T lymphocytes (CD8) play a crucial role in infection clearance, although the role of CD8 cytotoxicity in disease control has not been elucidated. Lesions of DCL patients have been shown to harbor low numbers of CD8, as compared to patients with LCL, and leishmanicidal treatment restores CD8 numbers. The marked response of CD8 towards Leishmania parasites led us to analyze possible functional differences between CD8 from patients with LCL and DCL. We compared IFNγ production, antigen-specific proliferation, and cytotoxicity of CD8 purified from PBMC against autologous macrophages (MO) infected with Leishmania mexicana (MOi). Additionally, we analyzed tissue biopsies from both groups of patients for evidence of cytotoxicity associated with apoptotic cells in the lesions. We found that CD8 cell of DCL patients exhibited low cytotoxicity, low antigen-specific proliferation and low IFNγ production when stimulated with MOi, as compared to LCL patients. Additionally, DCL patients had significantly less TUNEL+ cells in their lesions. These characteristics are similar to cellular “exhaustion” described in chronic infections. We intended to restore the functional capacity of CD8 cells of DCL patients by preincubating them with TLR2 agonists: Lm lipophosphoglycan (LPG) or Pam3Cys. Cytotoxicity against MOi, antigen-specific proliferation and IFNγ production were restored with both stimuli, whereas PD-1 (a molecule associated with cellular exhaustion) expression, was reduced. Our work suggests that CD8 response is associated with control of Lm infection in LCL patients and that chronic infection in DCL patients leads to a state of CD8 functional exhaustion, which could facilitate disease spread. This is the first report that shows the presence of functionally exhausted CD8 T lymphocytes in DCL patients and, additionally, that pre-stimulation with TLR2 ligands can restore the effector mechanisms of CD8 T lymphocytes from DCL patients against Leishmania mexicana-infected macrophages. Leishmania mexicana causes localized and diffuse cutaneous leishmaniasis. Whereas the former is a benign form the disease, diffuse cutaneous leishmaniasis is a chronic disfiguring disease, for which no cure is available, and the immune cells of these patients respond poorly to the parasite. It has been proposed that the elimination of Leishmania-infected cells by CD8 T cells is crucial for disease control. We compared the functional characteristics of CD8 T cells from patients with localized and diffuse cutaneous leishmaniasis. We found that CD8 T cells from patients with diffuse cutaneous leishmaniasis were functionally exhausted, as compared to patients with the benign form of the disease. We were able to restore functional capacity of these cells by culturing them with molecules that stimulate TLR2. This is the first report showing that stimulation of the TLR2 can restore effector mechanisms in functionally exhausted CD8 cells from patients with diffuse cutaneous leishmaniasis. This finding will help design novel treatment schemes for patients infected with the parasite Leishmania mexicana who have the progressive, incurable form of diffuse cutaneous leishmaniasis.
登录
查看更多内容
DOI：
10.4049/jimmunol.0800997
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bucks CM;Norton JA;Boesteanu AC;Mueller YM;Katsikis PD
通讯作者：
Katsikis PD
影响因子：
2.2
作者：
Herath, S;Kropf, P;Müller, I
通讯作者：
Müller, I
影响因子：
6.4
作者：
BADARO, R;JOHNSON, WD
通讯作者：
JOHNSON, WD
影响因子：
1.5
作者：
Becker, I;Salaiza, N;Isibasi, A
通讯作者：
Isibasi, A
影响因子：
64.8
作者：
Day, Cheryl L.;Kaufmann, Daniel E.;Walker, Bruce D.
通讯作者：
Walker, Bruce D.