CD56 as a marker of an ILC1-like population with NK cell properties that is functionally impaired in AML.

An understanding of natural killer (NK) cell physiology in acute myeloid leukemia (AML) has led to the use of NK cell transfer in patients, demonstrating promising clinical results. However, AML is still characterized by a high relapse rate and poor overall survival. In addition to conventional NKs that can be considered the innate counterparts of CD8 T cells, another family of innate lymphocytes has been recently described with phenotypes and functions mirroring those of helper CD4 T cells. Here, in blood and tissues, we identified a CD56+ innate cell population harboring mixed transcriptional and phenotypic attributes of conventional helper innate lymphoid cells (ILCs) and lytic NK cells. These CD56+ ILC1-like cells possess strong cytotoxic capacities that are impaired in AML patients at diagnosis but are restored upon remission. Their cytotoxicity is KIR independent and relies on the expression of TRAIL, NKp30, NKp80, and NKG2A. However, the presence of leukemic blasts, HLA-E-positive cells, and/or transforming growth factor-β1 (TGF-β1) strongly affect their cytotoxic potential, at least partially by reducing the expression of cytotoxic-related molecules. Notably, CD56+ ILC1-like cells are also present in the NK cell preparations used in NK transfer-based clinical trials. Overall, we identified an NK cell-related CD56+ ILC population involved in tumor immunosurveillance in humans, and we propose that restoring their functions with anti-NKG2A antibodies and/or small molecules inhibiting TGF-β1 might represent a novel strategy for improving current immunotherapies

Dopamine inhibits the effector functions of activated NK cells via the upregulation of the D5 receptor

Several lines of evidence indicate that dopamine (DA) plays a key role in the cross-talk between the nervous and immune systems. In this study, we disclose a novel immune-regulatory role for DA: inhibition of effector functions of activated NK lymphocytes via the selective upregulation of the D5 dopaminergic receptor in response to prolonged cell stimulation with rIL-2. Indeed, engagement of this D1-like inhibitory receptor following binding with DA suppresses NK cell proliferation and synthesis of IFN-\u3b3. The inhibition of IFN-\u3b3 production occurs through blocking the repressor activity of the p50/c-REL dimer of the NF-\u3baB complex. Indeed, the stimulation of the D5 receptor on rIL-2-activated NK cells inhibits the binding of p50 to the microRNA 29a promoter, thus inducing a de novo synthesis of this miRNA. In turn, the increased levels of microRNA 29a were inversely correlated with the ability of NK cells to produce IFN-\u3b3. Taken together, our findings demonstrated that DA switches off activated NK cells, thus representing a checkpoint exerted by the nervous system to control the reactivity of these innate immune effectors in response to activation stimuli and to avoid the establishment of chronic and pathologic inflammatory processes

Homeostasis of hepatic Natural Killer cells and their role in the physiopathology of liver metastasis of colon cancer

Natural Killer (NK) cells are innate lymphocytes that are critical in the defense against tumors and pathogens. They comprise up to 15% of total circulating lymphocytes but represent approximately 30% of the intra-hepatic lymphocytes. While the phenotype and functions of these cells have been extensively studied in peripheral blood (PB), a full characterization of resident hepatic NK cells (H-NK) is still lacking. Here we describe the phenotypic features of NK cells from specimens of healthy human liver obtained from patients undergoing surgical resections of liver metastasis of colo-rectal adenocarcinoma (CRA). The fact that these tissues specimens are free of any disease has been confirmed both macro- and microscopically. Additionally, the present study also compares the phenotype of tumor-infiltrating NK cells (TI-NK) with H-NK from the same donors. Our results show that the repertoire of activating and inhibitory NK cell receptors of resident H-NK cells is similar to that of both PB-NK and TI-NK cells within the same patients. However, we found a striking dissimilarity between PB-NK and H-NK in the expression of several surface molecules involved in the migration, adhesion and homing of NK cells. In contrast, very few differences were observed in the expression of these \u201choming\u201d molecules between H-NK and TI-NK. Also in line with what has been observed in PB-NK, the analyses of NK cell subsets in both healthy liver and metastatic lesions of CRA revealed the existence of two subsets of CD56pos/CD16neg and CD56pos/CD16pos expressing distinct receptor repertoires. This notwithstanding, while the ratio of CD56pos/CD16neg to CD56pos/CD16pos NK cells in PB is approximately 1:9, the one observed in healthy liver is 1:1. A similar 1:1 ratio of the two subsets is also maintained within NK cells infiltrating the liver metastasis of colon cancer, although the overall number of NK cells in tumor is significantly lower when compared to the frequency of resident hepatic NK cells. Despite the fact that the phenotype of TI-NK cells generally mirrors the one of H-NK, our data also demonstrate that \u3b15 integrin is significantly and highly up-regulated on TI-NK as compared to H-NK. Therefore, we hypothesize that the adhesion molecule \u3b15 integrin is involved in the retention of H-NK cells in the tumor microenvironment and that this biologic phenomenon might be associated with the reduction of tumor mass or a better prognosis of disease

NK cell recruitment in salivary glands provides early viral control but is dispensable for tertiary lymphoid structure formation.

Salivary glands (SGs) represent a permissive site for several sialotropic viruses whose persistence is linked to the development of autoimmunity. Natural Killer (NK) cells play a key role in viral clearance but their involvement in viral infection control and in tertiary lymphoid structures (TLS) development within SGs is unknown. By using an inducible model of TLS in the SGs of wild-type C57BL/6 mice, induced by the local delivery of a replication-defective adenovirus (AdV), we demonstrated that circulating NK cells are rapidly recruited to SGs and highly enrich the early inflammatory infiltrate prior to TLS development. NK cells migrating to SGs in response to AdV infection up-regulate NKp46, undergo proliferation, acquire cytotoxic potential, produce Granzyme-B and IFN-γ, and reduce viral load in the acute phase of the infection. Nonetheless, the selective depletion of both circulating and infiltrating NK cells in AdV-infected mice neither affect the development and frequency of TLS nor the onset of autoimmunity. These data demonstrate that, upon local viral delivery of AdV, peripheral NK cells homing to SGs can exert an early control of the viral infection but are dispensable for the formation of TLS and breach of immunologic tolerance

Increased Infiltration of Natural Killer and T Cells in Colorectal Liver Metastases Improves Patient Overall Survival

Introduction Cancer heterogeneity and degree of intra-tumoral immune cells represent variables affecting overall survival (OS). The present study investigated the impact of natural killer (NK) and T cells infiltrating colorectal liver metastases (CLM) in patients undergoing hepatectomy after neoadjuvant chemotherapy. Methods The frequencies of intra-tumoral, marginal, and peritumoral CD3+ T and NKp46+ NK cells were determined for 121 patients. OS was assessed in relation to prognostic factors. Results At univariate analysis, several variables, including T and N of the primary tumor, metachronous CLM, radiological response, and higher density of intra-tumoral CD3+ T cell (>1%/mm(2)) and of NKp46+ NK cells (>1 cell/mm(2)), were associated with OS. Only increased frequencies of intra-tumoral CD3+ Tcells (p = 0.005) and NKp46+ NK cells (p = 0.004) correlated with OS at multivariate analysis. The logistic regression revealed that metachronous CLM (OR = 2.781; p = 0.002), the use of an epidermal growth factor receptor inhibitor (OR = 3.891; p = 0.001), and radiological response (OR = 3.219; p = 0.001) were associated with higher infiltration of these cells. Conclusions High frequencies of NK and T cells in response to chemotherapy predict OS in CLM patients. These findings provide important insights that can help physicians to choose the best treatment option and adopt more predictive follow-up strategies for patients with CLM

Chronic ophthalmoparesis in limb girdle muscular dystrophy 1C.

No abstract available

The role of natural killer cells in autoimmune lIver disease : a comprehensive review

Natural Killer (NK) cells are important players of the innate arm of the immune system and provide an early defense against pathogens and tumor-transformed cells. Peripheral blood NK (PB-NK) cells were first identified because of their ability to spontaneously kill tumor-cell targets invitro without the need for specific antigen priming, which is the reason that they were named 'natural killer' cells. The characterization of NK cells in human tissues and body organs represented another important step forward to better understand their physiology and physiopathology. In this regard, many reports revealed over the past decade a differential anatomic distribution of NK cell subsets in several sites such as the intestine, lung, cervix, placenta and liver as well as in secondary lymphoid organs such as spleen, lymph nodes and tonsils. Among all these tissues, the liver is certainly unique as its parenchyma contains an unusually high number of infiltrating immune cells with 30-50% of total lymphocytes being NK cells. Given the constant liver intake of non-self antigens from the gastrointestinal tract via the portal vein, hepatic NK (H-NK) cells must retain a certain degree of tolerance in the context of their immune-surveillance against dangers to the host. Indeed, the breakdown of the tolerogenic state of the liver-associated immune system has been shown to induce autoimmunity. However, the role of NK cells during the course of autoimmune liver diseases is still being debated mainly because a complete characterization of H-NK cells normally resident in healthy human liver has not yet been fully disclosed. Furthermore, the differences in phenotype and functions between human and mouse H-NK cells often preclude translation of results obtained from murine models into experimental approaches to be performed in humans. Here, we provide an extensive characterization of the phenotype of H-NK cells physiologically resident in the human liver by both mentioning data available in literature and including a set of original results recently developed in our laboratory. We then review our current knowledge in regard to the contribution of H-NK cells in regulating local immune homeostasis and tolerance as well as in inducing the development of liver autoimmunity

Human liver-resident CD56bright/CD16neg NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways

RATIONALE: 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. OBJECTIVES: 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. FINDINGS: Nearly 50% of the entire liver NK cell population is composed of functionally relevant CD56(bright) lr-NK cells that localize within hepatic sinusoids. CD56(bright) 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. Here, we also show that hepatic sinusoids express CCL3(pos) Kupffer cells, CXCL16(pos) endothelial cells and CCL5(pos) T and NK lymphocytes. The selective presence of these chemokines in sinusoidal spaces creates a unique tissue niche for lr-CD56(bright) NK cells that constitutively express CCR5 and CXCR6. CD56(bright) lr-NK cells co-exist with CD56(dim) conventional NK (c-NK) cells that are, interestingly, transcriptionally and phenotypically similar to their peripheral circulating counterparts. Indeed, CD56(dim) c-NK cells lack expression of CD69, CCR5, and CXCR6 but express selectins, integrins and CX3CR1

Disulfiram neuropathy: Two cases of distal axonopathy

Background. Disulfiram may cause a peripheral neuropathy that is considered dose- and duration-of-exposure-related. Axonal degeneration has been described as a pathological hallmark of disulfiram toxicity, but experiments have reported a primary toxic effect of the molecule on Schwann cells and myelin. Case Reports. Case 1: At the end of two months of treatment with disulfiram 250 mg/day, a 31-year-old woman complained of weakness in distal segments of the lower limbs associated with burning dysesthesias, numbness and pain in the soles of the feet and the legs below the knees; bilateral walking steppage, reduction in foot strength, absence of ankle jerk and knee tendon reflexes, and tactile stocking pin-pick and vibratory sensory impairment in the lower limbs below the knee. Disulfiram was discontinued and she recovered partially over three months. Case 2: After one month of treatment with disulfiram 1600 mg/day, a 27-year-old man reported walking impairment, distal lower limb weakness and paresthesias. He had unsteady gait with bilateral steppage and foot drop, absence of ankle jerks and overall sensation impairment below the knee. Disulfiram was discontinued and nine months later there was almost complete recovery of motor deficits, only minor motor weakness in distal leg muscles, and no dysesthesia, sensation deficits or areflexia. In both of them clinical and neurophysiological patterns were indicative of a distal axonopathy. Discussion. The mechanisms by which disulfiram cause injury in human nerves are unclear, though may involve carbon disulfide. The discrepancy between experimental and clinical observations is still unexplained. Conclusion. We report two cases of disulfiram axonal toxicity and the partial response following discontinuation of the drug. Copyright © Informa Healthcare USA, Inc