Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30

Natural killer (NK) cells are part of the innate immunity repertoire, and function in the recognition and destruction of tumorigenic and pathogen-infected cells. Engagement of NK cell activating receptors can lead to functional activation of NK cells, resulting in lysis of target cells. NK cell activating receptors specific for non-major histocompatibility complex ligands are NKp46, NKp44, NKp30, NKG2D, and CD16 (also known as FcγRIII). The natural cytotoxicity receptors (NCRs), NKp46, NKp44, and NKp30, have been implicated in functional activation of NK cells following influenza virus infection via binding with influenza virus hemagglutinin (HA). In this review we describe NK cell and influenza A virus biology, and the interactions of influenza A virus HA and other pathogen lectins with NK cell natural cytotoxicity receptors (NCRs). We review concepts which intersect viral immunology, traditional virology and glycobiology to provide insights into the interactions between influenza virus HA and the NCRs. Furthermore, we provide expert opinion on future directions that would provide insights into currently unanswered questions.     

Altered NKp46 Recognition and Elimination of Influenza B Viruses

Every year, millions of people worldwide are infected with influenza, causing enormous health and economic problems. The most common type of influenza is influenza A. It is known that Natural Killer (NK) cells play an important role in controlling influenza A infection, mostly through the recognition of the viral protein hemagglutinin (HA) by the activating receptor, NKp46. In contrast, little is known regarding NK cell recognition of influenza B viruses, even though they are responsible for a third of all pediatric influenza deaths and are therefore included in the seasonal vaccine each year. Here we show that NKp46 also recognizes influenza B viruses. We show that NKp46 binds the HA protein of influenza B in a sialic acid-dependent manner, and identified the glycosylated residue in NKp46, which is critical for this interaction. We discovered that this interaction has a binding affinity approximately seven times lower than NKp46 binding of influenza A’s HA. Finally, we demonstrated, using mice deficient for the mouse orthologue of NKp46, named NCR1, that NKp46 is not important for influenza B elimination. These findings enable us to better understand the interactions between the different influenza viruses and NK cells that are known to be crucial for viral elimination.     

The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46

The destruction of viral-infected and tumor cells is mediated in part via the lysis receptor of natural killer (NK) cells, NKp46. The nature, however, of its lysis ligands expressed on target cells is poorly defined. Recently, we have identified a novel functional interaction between the lysis receptors NKp46 and NKp44 and the hemagglutinin of influenza and hemagglutinin-neuroaminidase of Sendai viruses. This recognition depends on the sialylation of NKp46 and NKp44 receptors. In this study, we expand the significance of these observations by demonstrating a conserved pattern of NKp46 and NKp44 recognition by various hemagglutinins derived from different viral strains. We further establish that this recognition is direct and mainly mediated via alpha2,6-linked sialic acid carried by NKp46. In addition, we demonstrate that the ability of NKp46 to recognize target cells is confined to the membrane proximal domain, and largely relies on the highly conserved sugar-carrying residue, Thr 225. This residue plays a critical dual role in NKp46 interactions with both viral hemagglutinins and the unknown tumor ligands via different mechanisms. These results may explain the ability of NK cells to kill such a broad spectrum of viral-infected and tumor cells.     

Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44

Natural killer (NK) cell-mediated cytotoxicity is triggered by multiple activating receptors associated with the signaling adaptor protein DNAX activation protein 12/killer cell-activating receptor-associated protein (DAP12/KARAP). Here, we show that one of these receptors, NKp44, is present on a subset of natural interferon-producing cells (IPCs) in tonsils. NKp44 expression can also be induced on blood IPCs after in vitro culture with interleukin 3 (IL-3). Crosslinking of NKp44 does not trigger IPC-mediated cytotoxicity but, paradoxically, inhibits interferon alpha (IFN-alpha) production by IPCs in response to cytosine-phosphate-guanosine (CpG) oligonucleotides. We find that IPCs in tonsils are in close contact with CD8+ T cells and demonstrate that a subset of memory CD8+ T cells produces IL-3. Therefore, IL-3-mediated induction of NKp44 on IPCs may be an important component of the ongoing crosstalk between the innate and adaptive immune response that allows memory CD8+ T cells to control the IPC response to virus.     

Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46

Natural killer (NK) cells contribute to a variety of innate immune responses to viruses, tumors and allogeneic cells. However, our understanding of NK cell biology is severely limited by the lack of consensus phenotypic definition of these cells across species, by the lack of specific marker to visualize them in situ, and by the lack of a genetic model where NK cells may be selectively ablated. NKp46/CD335 is an Ig-like superfamily cell surface receptor involved in human NK cell activation. In addition to human, we show here that NKp46 is expressed by NK cells in all mouse strains analyzed, as well as in three common monkey species, prompting a unifying phenotypic definition of NK cells across species based on NKp46 cell surface expression. Mouse NKp46 triggers NK cell effector function and allows the detection of NK cells in situ. NKp46 expression parallels cell engagement into NK differentiation programs because it is detected on all NK cells from the immature CD122(+)NK1.1(+)DX5(-) stage and on a minute fraction of NK-like T cells, but not on CD1d-restricted NKT cells. Moreover, human NKp46 promoter drives NK cell selective expression both in vitro and in vivo. Using NKp46 promoter, we generated transgenic mice expressing EGFP and the diphtheria toxin (DT) receptor in NK cells. DT injection in these mice leads to a complete and selective NK cell ablation. This model paves a way for the in vivo characterization and preclinical assessment of NK cell biological function.     

原发性小肠肿瘤44例临床分析

原发性小肠肿瘤非常少见，临床早期诊断困难。目的：探讨原发性小肠肿瘤的临床常见表现、诊断和治疗方法。方法：回顾性分析1990年1月-2007年1月北京友谊医院确诊的44例原发性小肠肿瘤患者的临床资料。结果：原发性小肠肿瘤患者男女比例为3：1。主要临床表现为柏油样便、腹部包块、腹痛和肠梗阻症状。原发性小肠肿瘤以空肠最为常见，良恶性比为1：3．4。44例原发性小肠肿瘤患者中，29例（65．9％）为间质瘤，其中良性6例，低度恶性7例，高度恶性16例；5例（11．4％）为非霍奇金淋巴瘤；4例（9．1％）为腺癌；3例（6．8％）为平滑肌瘤；1例（2_3％）为平滑肌肉瘤；1例（2．3％）为类癌；1例（2．3％）为绒毛管状腺瘤。所有患者均行手术治疗。结论：原发性小肠肿瘤临床表现无特异性，病理类型多样，结合常见临床表现和有效检查方法有助于尽早诊断该病。     

Interleukin-22 Secreted by NKp44+ Natural Killer Cells Promotes Proliferation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Although CD3-CD56+NKp44+ natural killer (NKp44+NK) cells have been linked to autoimmune diseases including inflammatory bowel disease, ankylosing spondylitis, and primary Sjogren syndrome, the expansion and role of those cells in patients with rheumatoid arthritis (RA) remain less defined. Here, we investigate the proportion and pathogenesis of NKp44+NK cells in patients with RA. The results show NKp44+NK cells significantly expanded in RA peripheral blood and synovial fluid, which were correlated positively with RA disease activity. They also highly expressed in RA synovial tissues and secreted a high concentration of interleukin-22 (IL-22) in vitro. Further, NKp44+NK cells culture supernatant promoted the proliferation of fibroblast-like synoviocytes (FLS) which was blocked by IL-22 antagonist and AG490. Treated with recombination human IL-22, the proliferation and phosphorylation-STAT3 on RA-FLS increased in a dose-dependent manner and time-dependent manner; the progress of which could be blocked by AG490. The present study clarifies the expansion of NKp44+NK cells in the peripheral blood and synovial fluid of patients with RA, especially in the synovial tissues of RA for the first time. STAT3 is an essential pathway in mediating the effects of IL-22 secreted by NKp44+NK cells on the proliferation of FLS in patients with RA.     

自身免疫性肝炎患者外周血NKp46+ILC3细胞和Th17细胞变化及其临床意义探讨*

目的 研究自身免疫性肝炎(AIH)患者外周血NKp46⁺ILC3细胞和Th17细胞百分比变化及其临床意义。方法 2016年2月～2020年2月我院收治的AIH患者43例,使用流式细胞仪检测外周血NKp46⁺3型天然淋巴样细胞(ILC3)和Th17细胞百分比,应用受试者工作特征曲线(ROC)下面积(AUC)分析应用NKp46⁺ILC3细胞和Th17细胞百分比判断AIH患者肝组织炎症活动分级的效能。结果 10例临床重度AIH患者NKp46⁺ILC3细胞和Th17细胞百分比分别为(0.2±0.2)%和(1.3±0.4)%,显著低于或高于33例轻中度AIH患者【分别为(0.5±0.2)%和(0.8±0.3)%,P<0.05】;12例肝组织G3～4级AIH患者 NKp46⁺ILC3细胞百分比和Th17细胞百分比分别为(0.3±0.2)%和(1.3±0.4)%,显著低于或高于31例G1～2级AIH患者【分别为(0.5±0.2)%和(0.8±0.3)%,P<0.05】;以外周血NKp46⁺ILC3细胞百分比≤0.3%为截断点,判断AIH患者肝组织炎症重度活动的AUC为0.774(95% CI:0.592～0.957),其敏感度为75.0%,特异度为87.1%;以外周血Th17细胞百分比＞1.1%为截断点,判断AIH患者肝组织炎症重度活动的AUC为0.853(95% CI:0.734～0.973),其敏感度为66.7%,特异度为90.3%。结论 AIH患者外周血NKp46⁺ILC3细胞水平降低,而Th17细胞水平升高。应用这种变化规律可能有助于判断AIH患者肝组织炎症活动分级,对评估AIH患者病情具有一定的临床意义。     

Intrahepatic natural killer cell NKp46 expression drives HCV-associated liver inflammation and viral resistance to treatment with interferon alpha

BackgroundThere is evidence that natural killer (NK) cells help control persistent viral infections including hepatitis C virus (HCV). HCV infection is treated with interferon (IFN) alpha, which stimulates the immune system, and is successful in 40–80% of patients. Detailed comparison of the phenotype and function of blood and intrahepatic NK cells in chronic HCV infection and in response to treatment with IFN alpha has not been elucidated.MethodsWe performed a comparison of NK cells derived from blood and intrahepatic compartments in multiple paired samples from 24 HCV infected patients pretreatment and 22 patients with non-viral chronic liver disease (CLD). NK phenotype (CD16, NKp30, NKp46, NKG2D, and NKG2A) and functional profile (CD107a, IFNγ, and granzyme B) were assessed with flow cytometry. In a separate cohort of 17 patients with HCV, who had completed treatment, rate of viral clearance was calculated and pretreatment peripheral blood NK phenotype and CD107a expression (degranulation) in response to increasing stimulation was measured.FindingsNK cells in the liver demonstrate a distinct phenotype compared with blood, manifested as downregulation of the NK cell activation receptors CD16, NKG2D, and NKp30. By contrast, NKp46 expression was not downregulated. Intrahepatic NK cells appeared to be more activated with increased spontaneous degranulation (reduced granzyme B, p<0·001 and increased CD107a, p=0·006) and production of IFNγ (p=0·05). NKp46 expression correlated with NK-cell activation, and correlated closely with the severity of liver inflammation (p=0·035). The rate of viral clearance during treatment with IFN alpha inversely correlated with NKp46 expression at baseline (p=0·01). However, the ability to increase cytotoxic NK function in response to increasing stimulation ex vivo correlated with viral clearance (p=0·029) and inversely with NKp46 (p=0·005).InterpretationThese findings indicate that NKp46 marks out pathologically activated NK cells in HCV, which are unlikely to be involved in viral control in IFN alpha-treated individuals.FundingWelsh Assembly.     

NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies

Information on natural killer (NK)-cell receptor-ligand interactions involved in the response to human cytomegalovirus (HCMV) is limited and essentially based on the study of infected fibroblasts. Experimental conditions were set up to characterize the NK response to HCMV-infected myeloid dendritic cells (DCs). Monocyte-derived DCs (moDCs) infected by the TB40/E HCMV strain down-regulated the expression of human leukocyte antigen class I molecules and specifically activated autologous NK-cell populations. NKG2D ligands appeared virtually undetectable in infected moDCs, reflecting the efficiency of immune evasion mechanisms, and explained the lack of antagonistic effects of NKG2D-specific monoclonal antibody. By contrast, DNAM-1 and DNAM-1 ligands (DNAM-1L)-specific monoclonal antibodies inhibited the NK response at 48 hours after infection, although the impact of HCMV-dependent down-regulation of DNAM-1L in infected moDCs was perceived at later stages. moDCs constitutively expressed ligands for NKp46 and NKp30 natural cytotoxicity receptors, which were partially reduced on HCMV infection; yet, only NKp46 appeared involved in the NK response. In contrast to previous reports in fibroblasts, human leukocyte antigen-E expression was not preserved in HCMV-infected moDCs, which triggered CD94/NKG2A(+) NK-cell activation. The results provide an insight on key receptor-ligand interactions involved in the NK-cell response against HCMV-infected moDCs, stressing the importance of the dynamics of viral immune evasion mechanisms.     

类风湿关节炎患者外周血及滑液NKp44+自然杀伤细胞的表达和临床意义探讨

目的 探讨类风湿关节炎(RA)患者外周血及滑液NKp44+自然杀伤细胞的临床意义.方法 采用流式细胞术检测20例活动期RA患者[疾病活动指数(DAS)28≥2.6]、15例缓解期RA患者(DAS28＜2.6)及20名健康对照者外周血NKp44+自然杀伤细胞比例及10例活动期RA患者滑液NKp44+自然杀伤细胞比例.多重非参数检验比较3组间NKp44+自然杀伤细胞比例差异.采用Spearmar相关分析NKp44+自然杀伤细胞与临床指标[DAS28评分、抗环瓜氨酸肽(CCP)抗体、类风湿因子(RF)]的相关性.结果 ①活动期、缓解期RA患者及健康对照者外周血NKp44+自然杀伤细胞比例分别为(1.480±4.750)%、(0.540±0.590)%、(0.000±0.000)%,活动期RA患者外周血NKp44+细胞比例明显高于缓解期和健康对照(x2=46.708,P=0.000).②10例活动期RA患者滑液NKp44+自然杀伤细胞比例为(15.6±11.7)%,明显高于其外周血NKp44+自然杀伤细胞比例(3.6±2.5)%(z=-3.780,P=0.000).③活动期RA患者外周血NKp44+自然杀伤细胞比例与DAS28评分、抗CCP抗体呈正相关(r=0.777,P=0.000;r=0.967,P=0.000),与RF无相关性(r=-0.343,P=0.138).滑液NKp44+自然杀伤细胞比例与DAS28评分、抗CCP抗体呈正相关(r=0.930,P=0.000;r=0.867,P=0.001),与RF无相关性(r=0.564,P=0.09).结论 NKp44+自然杀伤细胞在RA患者外周血及滑液中明显增高,且与DAS28评分、抗CCP抗体呈正相关,提示NKp44+自然杀伤细胞与疾病活动度和病情严重程度相关.

Abstract：

Objective To investigate the clinical significance of NKp44+NK cells in the peripheral blood and synovial fluid of rheumatoid arthritis (RA) patients.Methods The proportions of NKp44+NK cells in the PB of 20 active and 15 remission patients with RA and 20 healthy individuals were detected using flow cytometry.The proportions of NKp44+NK cells in the SF of 10 active patients were detected.Multiple nonparametric test was used to compared the difference of NKp44+NK cells proportions.Clinical data including DAS28,anti-CCP antibody and RF were collected.The relationship between NKp44+NK cells and clinical data was analyzed by Spearman correlation analysis.Results The proportions of NKp44+NK cells in PB of active and remission patients and healthy individuals were (1.480±4.750)%,(0.540±0.590)%,(0.000±0.000)%respectively.The proportion of NKp44+NK cells in PB of active patients was significantly higher than that of remission patients and healthy individuals (x2=46.708,P=0.000).The proportion of NKp44+NK cells in the SF of ten active RA patients was significantly higher than matched PB.There was positive correlation between NKp44+NK cells proportion in PB and SF of active patients and DAS 28 and anti-CCP antibody level.There was no correlation between NKp44+NK cells proportion in PB,SF and RF.Conclusion There is a marked increase in the proportion of NKp44+NK cells in PB and SF of RA patients.Moreover,NKp44+NK cells are positively correlated with DAS28 and anti-CCP antibody,suggesting that NKp44+NK cells may be correlated with disease activity and severity.     

Natural killer cells in HIV controller patients express an activated effector phenotype and do not up-regulate NKp44 on IL-2 stimulation

Control of HIV replication in elite controller (EC) and long-term nonprogressor (LTNP) patients has been associated with efficient CD8⁺cytotoxic T-lymphocyte function. However, innate immunity may play a role in HIV control. We studied the expression of natural cytotoxicity receptors (NKp46, NKp30, and NKp44) and their induction over a short time frame (2–4 d) on activation of natural killer (NK) cells in 31 HIV controller patients (15 ECs, 16 LTNPs). In EC/LTNP, induction of NKp46 expression was normal but short (2 d), and NKp30 was induced to lower levels vs. healthy donors. Notably, in antiretroviral-treated aviremic progressor patients (TAPPs), no induction of NKp46 or NKp30 expression occurred. More importantly, EC/LTNP failed to induce expression of NKp44, a receptor efficiently induced in activated NK cells in TAPPs. The specific lack of NKp44 expression resulted in sharply decreased capability of killing target cells by NKp44, whereas TAPPs had conserved NKp44-mediated lysis. Importantly, conserved NK cell responses, accompanied by a selective defect in the NKp44-activating pathway, may result in lack of killing of uninfected CD4⁺NKp44Ligand⁺ cells when induced by HIVgp41 peptide-S3, representing a relevant mechanism of CD4⁺ depletion. In addition, peripheral NK cells from EC/LTNP had increased NKG2D expression, significant HLA-DR up-regulation, and a mature (NKG2A−CD57⁺killer cell Ig-like receptor⁺CD85j⁺) phenotype, with cytolytic function also against immature dendritic cells. Thus, NK cells in EC/LTNP can maintain substantially unchanged functional capabilities, whereas the lack of NKp44 induction may be related to CD4 maintenance, representing a hallmark of these patients.A benign disease course with long-term nonprogressing disease (LTNP) up and beyond 20 y is observed in a minority (<1–2%) of HIV-1–infected patients who maintain high CD4⁺ T-cell counts (>500 µL) with low-level viremia (<1,000 cp/mL) without progression to AIDS in the absence of antiretroviral treatment (ART). A subset of LTNPs is aviremic virus-controlling (<50–75 cp/mL) patients who are considered to represent a distinct clinical entity defined as elite controllers (ECs) because of their efficient and extensive spontaneous control of viral replication (1, 2). Understanding of the mechanisms that underlie the lack of disease progression in EC and LTNP patients has attracted relevant scientific focus over the years, with the ultimate goal to exploit this understanding for therapeutic or vaccination purposes.Viral replication may be decreased in LTNP/EC because of virus mutations or host genetic background conferring reduced CD4⁺ T-cell susceptibility. However, both an intact viral replication capacity and a conserved CD4⁺ T-cell susceptibility to HIV infection in vitro have recently been proven in most HIV controller patients (3–5). Among cytotoxic effector cells, an acknowledged role in the control of viremia and disease has been attributed to CD8⁺ cytotoxic T lymphocytes (CTLs), which in these patients, display an exceptionally high avidity and breadth against HIV epitopes (1, 2, 6, 7). Vigorous and effective CTL responses associated to HLA class I haplotype (e.g., B*57 and B*27 alleles) represent an example of genetic background positively affecting HIV control (1, 2, 6, 7). Also, HLA-C polymorphisms have been implicated in the control of HIV (8). Unique allele carriage is, however, not a feature uniquely characterizing LTNPs/ECs. HIV controllers may lack this genetic background, but they have CTL responses with high avidity and breadth against HIV_gag. Conversely, this immunogenetic background may be present in progressors who display poorer CTL response quality (5, 9–11). Also, HLA B*5701 LTNPs/ECs and HLA-matched progressors cannot be distinguished by the clonal composition of HIV-specific CD8⁺ T cells (12).The relevance of natural killer (NK) cell function in the setting of HIV controller status has been suggested by genetic studies showing the association between HLA-Bw4_80I DNA carriage and specific killer cell Ig-like receptors (KIRs; i.e., KIR3DL1/S1) (13, 14). NK cell-associated control of HIV replication in vitro occurs with KIR3DS1⁺ NK cells in a HLA-Bw4_80I⁺ target cell genetic background (15); however, this result has not been subsequently reproduced in vivo in EC/LTNP cohorts (16). Various combinations of these mechanisms seem to be involved in the successful control of HIV replication in some LTNP and EC patients; however, none of them taken alone can fully explain this condition, and it has not been shown to identify all of these patients.Involvement of the activating NK receptors in disease progression was suggested by the demonstration that HIV-1 infection was associated to profoundly decreased expression of natural cytotoxicity receptors (NCRs; i.e., NKp46, NKp30, and NKp44) (17). This decrease, in turn, leads to an impaired cross-talk between NK cells and dendritic cells (DCs), resulting in an altered DC editing (18). Moreover, rates of CD4⁺ T-cell loss after ART interruption are inversely associated with NCR expression on NK cells before ART discontinuation (19).Interestingly, in the AIDS-free HIV infection model of chimpanzees, peripheral NK cells have absent/low baseline expression of NKp30, which was, however, inducible on cytokine-mediated in vitro NK cell activation (20). In addition, activating NK cell receptor induction/modulation has been reported in vivo and in vitro during treatment of human HCV infection involving NKp30 (21) and DNAX-accessory molecule 1 (DNAM-1,CD226) (22), which are both involved in DC–NK cell cross-talk (23, 24). In addition, activating NK cell receptor ligands are lost in CD4⁺ T cells of infected patients, with the exception of NKG2D-Ligands (e.g., MHC class I polypeptide-related sequence A/B,MICA/B) (25). Furthermore, HIV_nef and HIV_vpu have been shown to directly target NKG2D and DNAM-1 ligands (i.e., MICA/B and poliovirus receptor, PVR) (26, 27). These immune evasion mechanisms are in line with the idea that NK cells may exert a critical control of HIV-1 infection. In this context, an as yet uncharacterized NKp44-L is reported to be induced in uninfected CD4⁺ T cells by an HIV_gp41 peptide inducing innocent CD4⁺ T-cell bystander lysis (28, 29). These observations, thus, raise the question of whether differences in NCR surface expression may help to explain the different disease course observed in HIV controllers—LTNPs, ECs, or both.Here, we report a study addressing the activating NK cell receptors expression, their modulation, and the consequences on NK cell function in a cohort of HIV controller (LTNP and EC) patients. The data provide evidence that differences in inducibility/modulation of NCR may offer clues on how successful disease-free HIV-1 control may be achieved in these patients.     

Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection

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-γ, 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-γ 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.