NKG2D promotes CD8 T cell-mediated cytotoxicity and is associated with treatment failure in human cutaneous leishmaniasis.
NKG2D promotes CD8 T cell-mediated cytotoxicity and is associated with treatment failure in human cutaneous leishmaniasis.
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DOI：
10.1371/journal.pntd.0011552
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发表时间：
2023-08
影响因子：
3.8
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中科院分区：
文献类型：
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皮肤利什曼病的临床表现取决于寄生虫的持久性和宿主的免疫病理反应。虽然溶细胞性CD 8 T细胞不能控制寄生虫，但它们显著促进病理反应。在皮肤利什曼病小鼠模型中，我们先前发现NKG 2D在细胞溶解性CD 8 T细胞促进利什曼病病变的能力中发挥作用。在这里，我们研究了NKG 2D是否在人类疾病中发挥作用。我们发现，NKG 2D及其配体表达于L.在巴西感染的患者中，IL-15和IL-1β分别是驱动NKG 2D和NKG 2D配体表达的因素。阻断NKG 2D可减少患者亚组中CD 8 T细胞的脱粒。此外，我们对患者病变的转录分析发现，第一轮治疗失败的患者比治疗有反应的患者表现出更高的KLRK 1（编码NKG 2D的基因）表达。这些发现表明，NKG 2D可能是一个有前途的治疗靶点，用于改善由L.巴西人感染皮肤利什曼病是一种被忽视的热带疾病，每年报告的新病例超过20万例。L.巴西溃疡会导致慢性溃疡病变，常规治疗往往失败，因此需要新的疗法来控制该疾病。促进疾病增加和治疗失败的主要因素之一是细胞溶解性T细胞向皮肤病变的募集，其促进炎症增加而不控制寄生虫。本研究探讨了先天性受体NKG 2D在L.巴西患者。利用L.巴西患者中，我们证明了NKG 2D在利什曼病病变中表达，确定了促进NKG 2D和NKG 2D配体表达的因素，并发现NKG 2D基因表达与治疗失败相关。基于这些结果，我们提出靶向NKG 2D可能被认为是一种减轻L.巴西患者。
Cutaneous leishmaniasis exhibits a spectrum of clinical presentations dependent upon the parasites’ persistence and host immunopathologic responses. Although cytolytic CD8 T cells cannot control the parasites, they significantly contribute to pathologic responses. In a murine model of cutaneous leishmaniasis, we previously found that NKG2D plays a role in the ability of cytolytic CD8 T cells to promote disease in leishmanial lesions. Here, we investigated whether NKG2D plays a role in human disease. We found that NKG2D and its ligands were expressed within lesions from L. braziliensis-infected patients and that IL-15 and IL-1β were factors driving NKG2D and NKG2D ligand expression, respectively. Blocking NKG2D reduced degranulation by CD8 T cells in a subset of patients. Additionally, our transcriptional analysis of patients’ lesions found that patients who failed the first round of treatment exhibited higher expression of KLRK1, the gene coding for NKG2D, than those who responded to treatment. These findings suggest that NKG2D may be a promising therapeutic target for ameliorating disease severity in cutaneous leishmaniasis caused by L. braziliensis infection. Cutaneous leishmaniasis is a neglected tropical disease, with over 200,000 new cases reported annually. The disease caused by L. braziliensis leads to chronic ulcerated lesions that often fail conventional treatment, and thus, new therapies to control the disease are needed. One of the major factors promoting increased disease and treatment failure is the recruitment of cytolytic T cells to the cutaneous lesions, which promotes increased inflammation without controlling the parasites. This study explores the role of the innate receptor NKG2D in L. braziliensis patients. Using clinical samples from L. braziliensis patients, we demonstrate that NKG2D is expressed in leishmanial lesions, identify factors that promote NKG2D and NKG2D ligand expression, and find that NKG2D gene expression is associated with treatment failure. Based on these results, we propose that targeting NKG2D might be considered as a therapy to dampen disease severity in L. braziliensis patients.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
DOI：
10.1084/jem.20031051
发表时间：
2003-11-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Berg RE;Crossley E;Murray S;Forman J
通讯作者：
Forman J
影响因子：
8.8
作者：
Chu T;Tyznik AJ;Roepke S;Berkley AM;Woodward-Davis A;Pattacini L;Bevan MJ;Zehn D;Prlic M
通讯作者：
Prlic M
疱疹病毒FC受体FCR-1下调了NKG2D配体MOULT-1和H60。
DOI：
10.1084/jem.20060514
发表时间：
2006-08-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.5
作者：
Da-Cruz, Alda M.;Oliveira-Neto, Manoel P.;Coutinho, Sergio G.
通讯作者：
Coutinho, Sergio G.