66 research outputs found
Increased Infiltration of Natural Killer and T Cells in Colorectal Liver Metastases Improves Patient Overall Survival
No full textIntroduction 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
Dopamine inhibits the effector functions of activated NK cells via the upregulation of the D5 receptor
No full textSeveral 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-γ. The inhibition of IFN-γ production occurs through blocking the repressor activity of the p50/c-REL dimer of the NF-κB 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-γ. 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
Skewed B cell differentiation affects lymphoid organogenesis but not T cell-mediated autoimmunity
No full textSummary: B cell receptor (BCR) signalling determines B cell differentiation and may potentially alter T cell-mediated immune responses. In this study we used two transgenic strains of BCR-deficient mice expressing Epstein-Barr virus latent membrane protein (LMP)2A in B cells, where either follicular and marginal zone differentiation (DHLMP2A mice) or B-1 cell development (VHLMP2A mice) were supported, and evaluated the effects of skewed B lymphocyte differentiation on lymphoid organogenesis and T cell responses in vivo. Compared to wild-type animals, both transgenic strains displayed alterations in the composition of lymphoid organs and in the dynamics of distinct immune cell subsets following immunization with the self-antigen PLP185-206. However, ex-vivoT cell proliferation to PLP185-206 peptide measured in immunized DHLMP2A and VHLMP2A mice was similar to that detected in immunized control mice. Further, clinical expression of experimental autoimmune encephalitis in both LMP2A strains was identical to that of wild-type mice. In conclusion, mice with skewed B cell differentiation driven by LMP2A expression in BCR-negative B cells do not show changes in the development of a T cell mediated disease model of autoimmunity, suggesting that compensatory mechanisms support the generation of T cell responses
Increased Infiltration of Natural Killer and T Cells in Colorectal Liver Metastases Improves Patient Overall Survival
No full textNK cell recruitment in salivary glands provides early viral control but is dispensable for tertiary lymphoid structure formation
No full textSalivary 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
Homeostasis of hepatic Natural Killer cells and their role in the physiopathology of liver metastasis of colon cancer
No full textNatural 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 “homing” 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 α5 integrin is significantly and highly up-regulated on TI-NK as compared to H-NK. Therefore, we hypothesize that the adhesion molecule α5 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
Impact of APOL1 polymorphism and IL-1β priming in the entry and persistence of HIV-1 in human podocytes
No full textBackground
Patients of African ancestry with untreated HIV-1 infection and carrying the G1 or G2 kidney disease risk variants (Vs) at the APOL1 gene have a tenfold higher risk of developing HIV-associated nephropathy (HIVAN) compared to those with the non-risk wild type (WT) G0 variant. However, the mechanistic contribution of the APOL1 allelic state to kidney injury in HIV-1 infection remains to be elucidated.
Results
Non-risk WT APOL1 is associated with lower intracellular levels of HIV-1 in conditionally immortalized human podocytes, while the over expression of G1 or G2 risk Vs significantly increases viral accumulation. The priming of podocytes with exogenous IL-1β facilitates HIV-1 entry, via the up-regulation of DC-SIGN. The over expression of APOL1 G1 and G2 risk Vs in combination with an increase in IL-1β levels causes a greater increase in viral concentration than either condition alone. In turn, HIV-1 and exogenous IL-1β together induce a de novo secretion of endogenous IL-1β and an increase of APOL1 gene expression.
Conclusions
Our findings indicate that the presence of risk Vs of APOL1 is permissive of HIV-1 persistence in human podocytes in synergy with IL-1β, a cytokine that characterizes the inflammatory milieu of acute and chronic phases of HIV-1 infection. The elucidation of these molecular mechanisms explains, at least in part, the higher frequency of HIVAN in populations carrying the risk polymorphic genetic variant of APOL1 gene
Priming of human resting NK cells by autologous M1 macrophages via the engagement of IL-1b, IFN-β, and IL-15 pathways
No full textThe cross talk between NK cells and macrophages is emerging as a major line of defense against microbial infections and tumors. This study reveals a complex network of soluble mediators and cell-to-cell interactions allowing human classically activated (M1) macrophages, but not resting (M0) or alternatively activated (M2) macrophages, to prime resting autologous NK cells. In this article, we show that M1 increase NK cell cytotoxicity by IL-23 and IFN-β-dependent upregulation of NKG2D, IL-1b-dependent upregulation of NKp44, and trans-presentation of IL-15. Moreover, both IFN-β-dependent cis-presentation of IL-15 on NK cells and engagement of the 2B4-CD48 pathway are used by M1 to trigger NK cell production of IFN-γ. The disclosure of these synergic cellular mechanisms regulating the M1-NK cell cross talk provides novel insights to better understand the role of innate immune responses in the physiopathology of tumor biology and microbial infections
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