International audienceAlphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanisms largely ill-characterized. The pathogenesis of CHIKV was addressed in a prospective cohort study of 49 hospitalized patients from Reunion Island subsequently categorized into two distinct groups at 12 mo postinfection. Comprehensive analyses of the clinical and immunological parameters throughout the disease course were analyzed in either the “recovered” or the “chronic” groups to identify prognostic markers of arthritis-like pathology after CHIKV disease. We found that the chronic group consisted mainly of more elderly patients (\textgreater60 y) and with much higher viral loads (up to 1010 viruses per milliliter of blood) during the acute phase. Remarkably, a rapid innate immune antiviral response was demonstrated by robust dendritic/NK/CD4/CD8 cell activation and accompanied by a rather weak Th1/Th2 cytokine response in both groups. Interestingly, the antiviral immune response witnessed by high levels of IFN-α mRNA in PBMCs and circulating IL-12 persisted for months only in the chronic group. CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 mo postinfection surrounded by infiltrating NK and T cells (CD4++ but rare cytotoxic CD8). Fibroblast hyperplasia, strong angiogenesis, tissue lesions given the high levels of matrix metalloproteinase 2, and acute cell death [high cleaved poly(ADP-ribose) polymerase staining] were observed in the injured synovial tissue. These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment but with immunosuppressive function in a context of viral persistence

Both the innate and adaptive immune systems contribute to tumor immunosurveillance in mice and humans; however, there is a paucity of direct evidence of a role for natural killer (NK) cells in this important process. In this study, we investigated the intratumoral phenotypic profile and functions of NK cells in primary human tumor specimens of non-small cell lung carcinoma (NSCLC). We used in situ methods to quantify and localize NK cells using the NKp46 marker and we characterized their phenotype in blood, tumoral, and nontumoral samples of NSCLC patients. Intratumoral NK cells displayed a profound and coordinated alteration of their phenotype, with a drastic reduction of NK cell receptor expression specifically detected in the tumoral region. According to their altered phenotype, intratumoral NK cells exhibited profound defects in the ability to activate degranulation and IFN-g production. We found that the presence of NK cells did not impact the clinical outcome of patients with NSCLC. Finally, we showed that tumor cells heterogeneously express ligands for both activating and inhibitory NK receptors. Taken together, our results suggest that the NSCLC tumor microenvironment locally impairs NK cells, rendering them less tumorcidal and thereby supportive to cancer progression. Cancer Res; 71(16); 5412-22. Ó2011 AACR.

Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells. IntroductionNatural killer (NK) cells have the ability to kill targets without prior sensitization and their involvement in antiviral and antitumor immunity is well established [1,2]. Recent studies have demonstrated a high degree of functional heterogeneity in the NK-cell compartment attributable to a vast network of inhibitory or activating receptors that allow these cells to recognize target cells [3,4]. Killer cell immunoglobulin-like receptors (KIR) and CD94/NKG2 heterodimers are two major types of HLA class I binding receptors that regulate NK cell function [5,6]. Both these receptor-families exist in activating and inhibitory forms and contribute to the functional education of human NK cells by interactions with their cognate ligands [7], whereas KIR are expressed in a stochastic manner with a variegated distribution in the NK cell population [8,9], NKG2A is expressed on all CD56bright NK cells and disappears gradually during differentiation of CD56 dim NK cells [10,11]. NKG2C and NKG2A are covalently associated with CD94 [12]. Both NKG2A and NKG2C specifically interact with the non-classical MHC class-Ib molecule HLA-E, which is expressed at low levels on almost all nucleated cells, and presents peptides derived from signal sequences of other HLA class-I molecules [13]. The affinity of their interaction depends on the sequence of the HLA-E-bound nonamers and is higher for NKG2A than for NKG2C [14,15]. In the CD56 dim subset, NKG2C expression largely excludes NKG2A expression [10,16]. Expression of NKG2C is induced by co-culture with HCMV-infected fibroblasts and correlates with HCMV seropositivity in healthy donors [16,17]. Recently, NKG2C 1 NK cells were shown to expand during HIV and hantavirus infections in HCMV-seropositive patients, suggesting that HCMV may prime the NK-cell compartment for specific expansion of the NKG2C 1 subset upon additional viral encounters [18,19]. Two recent papers have demonstrated increased expression of NKG2C on NK cells in patients with chronic HBV and HCV infection [20,21]. Therefore, we choose this clinical setting to perform an in-depth characterization of the NKG2C 1 NK-cell subset. We show that NKG2C 1 CD56 dim NK cells are terminally differentiated, highly polyfunctional and display a clonal expression of inhib...