Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways.
Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways.
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DOI：
10.1016/j.jaut.2015.08.011
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发表时间：
2016-01
影响因子：
12.8
通讯作者：
Mavilio D
中科院分区：
文献类型：
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作者：
Hudspeth K;Donadon M;Cimino M;Pontarini E;Tentorio P;Preti M;Hong M;Bertoletti A;Bicciato S;Invernizzi P;Lugli E;Torzilli G;Gershwin ME;Mavilio D
肝脏特异性自然杀伤（NK）细胞群体对于局部先天免疫应答至关重要，但导致其选择性归巢的机制及其功能相关性的定义仍然是个谜。我们利用健康人肝脏的可用性来严格定义调节NK细胞归巢至肝脏的机制以及区分肝脏驻留NK（lr-NK）细胞与循环对应物的受体库。整个肝脏NK细胞群体的近50%由位于肝窦内的功能相关的CD 56 bright lr-NK细胞组成。此外，CD 56 bright lr-NK细胞表达CD 69、CCR 5和CXCR 6，并且这种独特的趋化因子受体库在功能上是关键的，因为它决定了响应于由CCL 3、CCL 5和CXCL 16施加的趋化刺激的选择性迁移。此外，肝血窦表达CCL 3 pos枯否细胞、CXCL 16 pos内皮细胞和CCL 5 pos T和NK淋巴细胞。这些趋化因子在窦状隙中的选择性存在为组成性表达CCR 5和CXCR 6的lr-CD 56 bright NK细胞创造了组织小生境。CD 56 bright lr-NK细胞与CD 56 dim常规NK（c-NK）细胞共存，有趣的是，其在转录和表型上与其外周循环对应物相似。事实上，CD 56 dim c-NK细胞缺乏CD 69、CCR 5和CXCR 6的表达，但表达选择素、整联蛋白和CX 3CR 1。我们的发现揭示了lr-NK细胞和c-NK细胞之间的表型和功能差异，这对于区分肝脏特异性先天免疫应答至关重要。因此，修饰大的CD 56亮lr-NK细胞群体的任何治疗尝试将需要修饰肝CCR 5和CXCR 6。
The liver-specific natural killer (NK) cell population is critical for local innate immune responses, but the mechanisms that lead to their selective homing and the definition of their functionally relevance remain enigmatic. We took advantage of the availability of healthy human liver to rigorously define the mechanisms regulating the homing of NK cells to liver and the repertoire of receptors that distinguish liver-resident NK (lr-NK) cells from circulating counterparts. Nearly 50% of the entire liver NK cell population is composed of functionally relevant CD56bright lr-NK cells that localize within hepatic sinusoids. Further, CD56bright lr-NK cells express CD69, CCR5 and CXCR6 and this unique repertoire of chemokine receptors is functionally critical as it determines selective migration in response to the chemotactic stimuli exerted by CCL3, CCL5 and CXCL16. In addition, hepatic sinusoids express CCL3pos Kupffer cells, CXCL16pos endothelial cells and CCL5pos T and NK lymphocytes. The selective presence of these chemokines in sinusoidal spaces creates a tissue niche for lr-CD56bright NK cells that constitutively express CCR5 and CXCR6. CD56bright lr-NK cells co-exist with CD56dim conventional NK (c-NK) cells that are, interestingly, transcriptionally and phenotypically similar to their peripheral circulating counterparts. Indeed, CD56dim c-NK cells lack expression of CD69, CCR5, and CXCR6 but express selectins, integrins and CX3CR1. Our findings disclosing the phenotypic and functional differences between lr-Nk cells and c-NK cells are critical to distinguish liver-specific innate immune responses. Hence, any therapeutic attempts at modifying the large population of CD56bright lr-NK cells will require modification of hepatic CCR5 and CXCR6.