NKp46+CD3- natural killer lymphocytes isolated from blood, lymphoid organs, lung, liver and uterus can produce granule-dependent cytotoxicity and interferon-gamma. Here we identify in dermis, gut lamina propria and cryptopatches distinct populations of NKp46+CD3- cells with a diminished capacity to degranulate and produce interferon-gamma. In the gut, expression of the transcription factor RORgammat, which is involved in the development of lymphoid tissue-inducer cells, defined a previously unknown subset of NKp46+CD3- lymphocytes. Unlike RORgammat- lamina propria and dermis natural killer cells, gut RORgammat+NKp46+ cells produced interleukin 22. Our data show that lymphoid tissue-inducer cells and natural killer cells shared unanticipated similarities and emphasize the heterogeneity of NKp46+CD3- cells in innate immunity, lymphoid organization and local tissue repair.

Natural killer (NK) cells are large granular lymphocytes of the innate immune system that participate in the early control of microbial infections and cancer. NK cells can induce the death of autologous cells undergoing various forms of stress, recognizing and providing non-microbial 'danger' signals to the immune system. NK cells are widely distributed in lymphoid and non-lymphoid organs. NK cell precursors originate from the bone marrow and go through a complex maturation process that leads to the acquisition of their effector functions, to changes in their expression of integrins and chemotactic receptors, and to their redistribution from the bone marrow and lymph nodes to blood, spleen, liver, and lung. Here, we describe the tissue localization of NK cells, using NKp46 as an NK cell marker, and review the current knowledge on the mechanisms that govern their trafficking in humans and in mice.

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T-cells play a crucial role in progression of autoimmunity, including vitiligo, yet the initial steps triggering their activation and tissue damage remain unknown. Here we demonstrate increased presence of type-1 innate lymphoid cells (NK and ILC1)-producing interferon gamma (IFNγ) in the blood and in non-lesional skin of vitiligo patients. Melanocytes of vitiligo patients have strong basal expression of chemokine-receptor-3 (CXCR3) isoform B which is directly regulated by IFNγ. CXCR3B activation by CXCL10 at the surface of cultured human melanocytes induces their apoptosis. The remaining melanocytes, activated by the IFNγ production, express co-stimulatory markers which trigger T-cell proliferation and subsequent anti-melanocytic immunity. Inhibiting the CXCR3B activation prevents this apoptosis and the further activation of T cells. Our results emphasize the key role of CXCR3B in apoptosis of melanocytes and identify CXCR3B as a potential target to prevent and to treat vitiligo by acting at the early stages of melanocyte destruction.

Although dendritic cells (DCs) regulate immune responses, they exhibit functional heterogeneity depending on their anatomical location. We examined the functional properties of intestinal DCs after oral administration of cholera toxin (CT), the most potent mucosal adjuvant. Two CD11c+ DC subsets were identified both in Peyer’s patches and mesenteric lymph nodes (MLN) based on the expression of CD8α (CD8+ and CD8− DCs, respectively). A third subset of CD11c+CD8int was found exclusively in MLN. Feeding mice with CT induced a rapid and transient mobilization of a new CD11c+CD8− DC subset near the intestinal epithelium. This recruitment was associated with an increased production of the chemokine CCL20 in the small intestine and was followed by a massive accumulation of CD8int DCs in MLN. MLN DCs from CT-treated mice were more potent activators of naive T cells than DCs from control mice and induced a Th2 response. This increase in immunostimulating properties was accounted for by CD8int and CD8− DCs, whereas CD8+ DCs remained insensitive to CT treatment. Consistently, the CD8int and CD8− subsets expressed higher levels of costimulatory molecules than CD8+ and corresponding control DCs. Adoptive transfer experiments showed that these two DC subsets, unlike CD8+ DCs, were able to present Ags orally coadministered with CT in an immunostimulating manner. The ability of CT to mobilize immature DCs in the intestinal epithelium and to promote their emigration and differentiation in draining lymph nodes may explain the exceptional adjuvant properties of this toxin on mucosal immune responses.

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Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD), the main cause of chronic liver complications. The development of NASH is the consequence of aberrant activation of hepatic conventional immune, parenchymal, and endothelial cells in response to inflammatory mediators from the liver, adipose tissue, and gut. Hepatocytes, Kupffer cells and liver sinusoidal endothelial cells contribute to the significant accumulation of bone-marrow derived-macrophages and neutrophils in the liver, a hallmark of NASH. The aberrant activation of these immune cells elicits harmful inflammation and liver injury, leading to NASH progression. In this review, we highlight the processes triggering the recruitment and/or activation of hepatic innate immune cells, with a focus on macrophages, neutrophils, and innate lymphoid cells as well as the contribution of hepatocytes and endothelial cells in driving liver inflammation/fibrosis. On-going studies and preliminary results from global and specific therapeutic strategies to manage this NASH-related inflammation will also be discussed.

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