Natural killer cell responses to infections in early life.

Natural killer (NK) cells are an important component of innate immune responses to infectious diseases. They mediate protection by being able to rapidly lyse infected cells and produce cytokines (primarily interferon-γ) that shape innate and adaptive immune responses. This review summarizes current knowledge on the phenotype and functional abilities of NK cells from healthy newborns/infants and on NK cell responses against viral, bacterial and protozoan infections in early life. Interestingly, NK cell blood counts are higher in newborns than in adults but they do not display striking differences in phenotype, except for an increased frequency of expression of the inhibitory CD94/NKG2A receptor. They display some inherent functional defects, mainly a lower cytolytic capacity that may contribute to the immaturity of the neonatal immune system. Changes in circulating levels of NK cells observed during pediatric infections and the ability of NK cells from newborns and children to produce interferon-γ at the encounter with pathogens indicate that NK cells participate in the immune response to infectious diseases in early life. Unfortunately, information is currently insufficient to assess whether these NK cell responses really contribute to control infections, either vertically transmitted or acquired in infancy.Journal ArticleResearch Support, Non-U.S. Gov'tReviewSCOPUS: re.jinfo:eu-repo/semantics/publishe

Receptors and Cofactors That Contribute to SARS-CoV-2 Entry: Can Skin Be an Alternative Route of Entry?

To prevent the spread of SARS-CoV-2, all routes of entry of the virus into the host must be mapped. The skin is in contact with the external environment and thus may be an alternative route of entry to transmission via the upper respiratory tract. SARS-CoV-2 cell entry is primarily dependent on ACE2 and the proteases TMPRSS2 or cathepsin L but other cofactors and attachment receptors have been identified that may play a more important role in specific tissues such as the skin. The continued emergence of new variants may also alter the tropism of the virus. In this review, we summarize current knowledge on these receptors and cofactors, their expression profile, factors modulating their expression and their role in facilitating SARS-CoV-2 infection. We discuss their expression in the skin and their possible involvement in percutaneous infection since the presence of the virus has been detected in the skin

Killer cell immunoglobulin-like receptor expression induction on neonatal CD8+ T cells in vitro and following congenital infection with Trypanosoma cruzi

Major histocompatibility complex (MHC) class I-specific inhibitory natural killer receptors (iNKRs) are expressed by subsets of T cells but the mechanisms inducing their expression are poorly understood, particularly for killer-cell immunoglobulin-like receptors (KIRs). The iNKRs are virtually absent from the surface of cord blood T cells but we found that KIR expression could be induced upon interleukin-2 stimulation in vitro. In addition, KIR expression was enhanced after treatment with 5-aza-2′-deoxycytidine, suggesting a role for DNA methylation. In vivo induction of KIR expression on cord blood T cells was also observed during a human congenital infection with Trypanosoma cruzi which triggers activation of fetal CD8+ T cells. These KIR+ T cells had an effector and effector/memory phenotype suggesting that KIR expression was consecutive to the antigenic stimulation; however, KIR was not preferentially found on parasite-specific CD8+ T cells secreting interferon-γ upon in vitro restimulation with live T. cruzi. These findings show that KIR expression is likely regulated by epigenetic mechanisms that occur during the maturation process of cord blood T cells. Our data provide a molecular basis for the appearance of KIRs on T cells with age and they have implications for T-cell homeostasis and the regulation of T-cell-mediated immune responses

Primed antigen-specific CD4+ T cells are required for NK cell activation in vivo upon Leishmania major infection.

International audienceThe ability of NK cells to rapidly produce IFN-gamma is an important innate mechanism of resistance to many pathogens including Leishmania major. Molecular and cellular components involved in NK cell activation in vivo are still poorly defined, although a central role for dendritic cells has been described. In this study, we demonstrate that Ag-specific CD4(+) T cells are required to initiate NK cell activation early on in draining lymph nodes of L. major-infected mice. We show that early IFN-gamma secretion by NK cells is controlled by IL-2 and IL-12 and is dependent on CD40/CD40L interaction. These findings suggest that newly primed Ag-specific CD4(+) T cells could directly activate NK cells through the secretion of IL-2 but also indirectly through the regulation of IL-12 secretion by dendritic cells. Our results reveal an unappreciated role for Ag-specific CD4(+) T cells in the initiation of NK cell activation in vivo upon L. major infection and demonstrate bidirectional regulations between innate and adaptive immunity

NKp46+ Innate Lymphoid Cells Dampen Vaginal CD8 T Cell Responses following Local Immunization with a Cholera Toxin-Based Vaccine

International audienceInnate and adaptive immune cells work in concert to generate efficient protection at mucosal surface. Vaginal mucosa is an epithelial tissue that contains innate and adaptive immune effector cells. Our previous studies demonstrated that vaginal administration of Cholera toxin -based vaccines generate antigen-specific CD8 T cells through the stimulation of local dendritic cells (DC). Innate lymphoid cells (ILC) are a group of lymphocytes localized in epithelial tissues that have important immune functions against pathogens and in tissue homeostasis. Their contribution to vaccine-induced mucosal T cell responses is an important issue for the design of protective vaccines. We report here that the vaginal mucosa contains a heterogeneous population of NKp46+ ILC that includes conventional NK cells and ILC1-like cells. We show that vaginal NKp46+ ILC dampen vaccine-induced CD8 T cell responses generated after local immunization. Indeed, in vivo depletion of NKp46+ ILC with anti-NK1.1 antibody or NKG2D blockade increases the magnitude of vaginal OVA-specific CD8 T cells. Furthermore, such treatments also increase the number of DC in the vagina. NKG2D ligands being expressed by vaginal DC but not by CD8 T cells, these results support that NKp46+ ILC limit mucosal CD8 T cell responses indirectly through the NKG2D-dependent elimination of vaginal DC. Our data reveal an unappreciated role of NKp46+ ILC in the regulation of mucosal CD8 T cell responses

Functional properties of vaginal Eomes⁺ NK cells and Eomes^- ILC1-like cells.

<p>(A) Bidimensional dot plots (left panel) show expression of CD27 and CD11b on gated Eomes⁺ NKp46⁺ CD3^- cells from spleen, GLN and vaginas of naive C57BL/6 mice. Numbers in quadrants represent the percentage of cells for each subset. Histograms bars (right panel) represent results from five independent experiments expressed as mean values + SEM, <i>n</i> = 10 mice. <i>**p<0</i>.<i>01</i>, <i>***p<0</i>.<i>001</i>, <i>****p<0</i>.<i>0001</i> Mann-Whitney <i>U</i> test. Spl.: spleen; GLN: genital lymph nodes; Vag.: vagina. Frequencies of CD107a⁺ and IFN-γ⁺ producing Eomes⁺ NK cells (B) and Eomes^- ILC1-like cells (C) in cell suspensions from spleen, GLN and vagina of naive C57BL/6 mice. Cells (0.5 million/well) were stimulated <i>in vitro</i> for 4 hours with plate-bound isotype control (IC), anti NK1.1 mAb, PMA/ionomycin, IL-12 + IL-18 cytokines or YAC-1 tumor cells. CD107a and IFN-γ expression on cells were assessed by flow cytometry. Histogram bars represent results from three independent experiments expressed as mean percentages + SEM, <i>n</i> = 5 mice. <i>**p<0</i>.<i>01</i>, <i>***p<0</i>.<i>001</i>, Mann-Whitney <i>U</i> test. (D) Bidimensional dot plots (left panel) show expression of TNFα and TRAIL on gated Eomes^- ILC1 and Eomes⁺ NK cells from liver and vaginas of naive C57BL/6 mice after stimulation <i>in vitro</i> for 4 hours with PMA/ionomycin. Numbers in quadrants represent the percentage of cells for each subset. Results are representative of two independent experiments with n = 4 mice.</p

Vaginal NKp46⁺ CD3^- cell population contains conventional Eomes⁺ NK cells and Eomes^- ILC1-like cells.

<p>(A) Histogram plots show stainings with antibodies against specific markers (black line histograms) and with isotype control antibodies (grey line histograms) gated on NKp46⁺ CD3^- cells from spleen, GLN, and vagina of naive C57BL/6 mice. Specific stainings were also performed on NKp46⁺ CD3^- cells from liver and thymus. Numbers in histogram plots represent the MFI (mean fluorescence intensity) and the percentages of positive cells for the marker. Data are representative of at least four independent experiments. (B) Bidimensional dot plots show expression of CD49a and Eomes (upper panel) and CD49a and CD49b on gated NKp46⁺ CD3^- cells from spleen, GLN, vaginas and liver of naive C57BL/6 mice. Numbers in quadrants represent the percentage of cells for each subset.</p

Identification of vaginal NKp46⁺ CD3^- cells.

<p>(A) Frequencies (left panel) and numbers (right panel) of NKp46⁺ CD3^- cells among CD45⁺ leukocytes from spleen, genital lymph nodes (GLN) and vagina of naive C57BL/6 mice. Histogram plots represent results from five independent experiments and are expressed as mean values + SEM, <i>n</i> = 10 mice. (B) Immunofluorescence staining of frozen sections from mouse vagina and spleen stained with anti-CD3 (green) and anti-NKp46 (red) antibodies. Nuclei were visualized with DAPI (blue). White arrows indicate NKp46⁺ CD3^- cells; E: epithelium; LP: lamina propria. WP: white pulp; RP: red pulp. White dotted lines delineate the epithelium from the lamina propria in the vagina and the white pulp from the red pulp in the spleen. Original magnification: x40 (vagina) and x20 (spleen). Data are representative of three independent experiments.</p