Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection
Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection
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DOI：
10.1182/blood-2011-04-347260
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发表时间：
2011-09-22
期刊：
影响因子：
20.3
通讯作者：
Johnson, R. Paul
中科院分区：
文献类型：
--
作者：
Reeves, R. Keith;Rajakumar, Premeela A.;Johnson, R. Paul
自然杀伤（NK）细胞被经典地视为杀死病毒感染的细胞和肿瘤细胞的效应细胞，但最近的研究已经鉴定了分泌TH 17细胞因子IL-22的罕见粘膜NK细胞亚群。在这里，我们报告了2种不同的粘膜NK细胞谱系的鉴定，其特征为NKG 2A（+）NFIL 3（+）RORC（-）和NKp 44（+）NFIL 3（+）RORC（+）。NKG 2A（+）NK细胞全身分布、具有细胞毒性并分泌IFN-γ，而NKp 44（+）NK细胞是粘膜限制性、无细胞毒性并产生IL-22和IL-17。在SIV感染期间，NKp 44（+）NK细胞变得凋亡，被耗尽，并且具有改变的功能特征，其特征在于IL-17分泌减少; IFN-γ分泌增加;并且令人惊讶地，细胞毒性的可能性增加。NKp 44（+）NK细胞没有显示直接SIV感染的证据;相反，消耗和功能改变与SIV诱导的肠道炎症介质（包括吲哚胺2，3-双加氧酶1）上调相关。此外，在体外用吲哚胺2，3-双加氧酶1催化剂处理NKp 44（+）NK细胞以剂量依赖性方式减少IL-17的产生，而其他NK细胞功能不受影响。因此，慢病毒感染消耗和修改参与维持肠道完整性的粘膜NK细胞的功能库，这一发现突出了这种罕见的粘膜NK细胞群体的可塑性。（血。2011;118（12）：3321-3330）
Natural killer (NK) cells are classically viewed as effector cells that kill virus-infected and neoplastic cells, but recent studies have identified a rare mucosal NK-cell subpopulation secreting the TH17 cytokine IL-22. Here, we report identification of 2 distinct lineages of mucosal NK cells characterized as NKG2A(+)NFIL3(+)RORC(-) and NKp44(+)NFIL3(+)RORC(+). NKG2A(+) NK cells were systemically distributed, cytotoxic, and secreted IFN-gamma, whereas NKp44(+) NK cells were mucosae-restricted, noncytotoxic, and produced IL-22 and IL-17. During SIV infection, NKp44(+) NK cells became apoptotic, were depleted, and had an altered functional profile characterized by decreased IL-17 secretion; increased IFN-gamma secretion; and, surprisingly, increased potential for cytotoxicity. NKp44(+) NK cells showed no evidence of direct SIV infection; rather, depletion and altered function were associated with SIV-induced up-regulation of inflammatory mediators in the gut, including indoleamine 2,3-dioxygenase 1. Furthermore, treatment of NKp44(+) NK cells with indoleamine 2,3-dioxygenase 1 catabolites in vitro ablated IL-17 production in a dose-dependent manner, whereas other NK-cell functions were unaffected. Thus lentiviral infection both depletes and modifies the functional repertoire of mucosal NK cells involved in the maintenance of gut integrity, a finding that highlights the plasticity of this rare mucosal NK-cell population. (Blood. 2011;118(12):3321-3330)