Immunology - though deeply experimental in everyday practice - is also a theoretical discipline. Recent advances in the understanding of innate immunity, how it is triggered and how it shares ...features that have previously been uniquely ascribed to the adaptive immune system, can contribute to the refinement of the theoretical framework of immunology. In particular, natural killer cells and macrophages are activated by transient modifications, but adapt to long-lasting modifications that occur in the surrounding tissue environment. This process facilitates the maintenance of self-tolerance while permitting efficient immune responses. In this Essay we extend this idea to other components of the immune system and we propose some general principles that lay the foundations for a unifying theory of immunity - the discontinuity theory. According to this theoretical framework, effector immune responses (namely, activated responses that lead to the potential elimination of the target antigen) are induced by an antigenic discontinuity; that is, by the sudden modification of molecular motifs with which immune cells interact.
Summary
The activities of the immune system in repairing tissue injury and combating pathogens were long thought to be independent of the nervous system. However, a major regulatory role of ...immunomodulatory molecules released locally or systemically by the neuroendocrine system has recently emerged. A number of observations and discoveries support indeed the notion of the nervous system as an immunoregulatory system involved in immune responses. Innate lymphoid cells (ILCs), including natural killer (NK) cells and tissue‐resident ILCs, form a family of effector cells present in organs and mucosal barriers. ILCs are involved in the maintenance of tissue integrity and homeostasis. They can also secrete effector cytokines rapidly, and this ability enables them to play early roles in the immune response. ILCs are activated by multiple pathways including epithelial and myeloid cell‐derived cytokines. Their functions are also regulated by mediators produced by the nervous system. In particular, the peripheral nervous system, through neurotransmitters and neuropeptides, works in parallel with the hypothalamic‐pituitary‐adrenal and gonadal axis to modulate inflammatory events and maintain homeostasis. We summarize here recent findings concerning the regulation of ILC activities by neuroendocrine mediators in homeostatic and inflammatory conditions.
Controlling the balance between immunity and immunopathology is crucial for host resistance to pathogens. After infection, activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to the ...production of glucocorticoids. However, the pleiotropic effects of these steroid hormones make it difficult to delineate their precise role(s) in vivo. Here we found that the regulation of natural killer (NK) cell function by the glucocorticoid receptor (GR) was required for host survival after infection with mouse cytomegalovirus (MCMV). Mechanistically, endogenous glucocorticoids produced shortly after infection induced selective and tissue-specific expression of the checkpoint receptor PD-1 on NK cells. This glucocorticoid-PD-1 pathway limited production of the cytokine IFN-γ by spleen NK cells, which prevented immunopathology. Notably, this regulation did not compromise viral clearance. Thus, the fine tuning of NK cell functions by the HPA axis preserved tissue integrity without impairing pathogen elimination, which reveals a novel aspect of neuroimmune regulation.
Surface density of CD27 and CD11b subdivides mouse natural killer (NK) cells into 4 subsets: CD11blowCD27low, CD11blowCD27high, CD11bhighCD27high, and CD11bhighCD27low. To determine the developmental ...relationship between these 4 subsets, we used several complementary approaches. First, we took advantage of NDE transgenic mice that express enhanced green fluorescent protein (EGFP) and diphtheria toxin receptor specifically in NK cells. Diphtheria toxin injection leads to a transient depletion of NK cells, allowing the monitoring of the phenotype of developing EGFP+ NK cells after diphtheria toxin injection. Second, we evaluated the overall proximity between NK-cell subsets based on their global gene profile. Third, we compared the proliferative capacity of NK-cell subsets at steady state or during replenishment of the NK-cell pool. Fourth, we performed adoptive transfers of EGFP+ NK cell subsets from NDE mice into unirradiated mice and followed the fate of transferred cells. The results of these various experiments collectively support a 4-stage model of NK-cell maturation CD11blowCD27low → CD11blowCD27high → CD11bhighCD27high → CD11bhighCD27low. This developmental program appears to be associated with a progressive acquisition of NK-cell effector functions.
Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific ...killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer.
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•NK cell engagers are multifunctional Abs targeting tumor antigens, NKp46 and CD16•NKCEs bring tumor cells and NK cells together and trigger tumor-cell destruction•NKCEs can show killing potency superior to therapeutic Abs in vitro and in vivo•NKCEs may improve benefit-risk profile for cancer treatment compared to BiTEs
Trifunctional antibodies that engage natural killer cells by binding NKp46 and CD16, in addition to an antigen on cancer cells, show higher potency than current clinically available therapeutic antibodies.
Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the ...metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and positively fed back on the receptor for IL-15. This process was essential for sustaining NK cell proliferation during development and the acquisition of cytolytic potential during inflammation or viral infection. The mTORC1 inhibitor rapamycin inhibited NK cell cytotoxicity both in mice and humans; this probably contributes to the immunosuppressive activity of this drug in different clinical settings.
Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity ...across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease.
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•scRNA-seq on spleen and blood NK cells reveals organ-specific signatures•scRNA-seq reveals the heterogeneity of NK cells in the blood and spleen•scRNA-seq on NK cells defines NK1 as human CD56dim and mouse CD27−CD11b+ NK cells•scRNA-seq on NK cells defines NK2 as human CD56bright and mouse CD27+CD11b− NK cells
Several NK cell subsets have been reported in humans and mice, but their heterogeneity remains poorly characterized. Using high-throughput single-cell RNA-seq, Crinier et al. provide conserved tissue-specific gene signatures of NK cells from spleen and blood and identified two major NK cell subsets transcriptionally similar across organs and species.
The brave new world of innate lymphoid cells Eberl, Gérard; Di Santo, James P; Vivier, Eric
Nature immunology,
01/2015, Volume:
16, Issue:
1
Journal Article, Conference Proceeding
Peer reviewed
Researchers gathered in Paris at the first European Molecular Biology Organization conference devoted to innate lymphoid cells and discussed recent advances to further understanding of the ...development, regulation and function of these intriguing cells.
•NK cell cytotoxicity is regulated by an array of activating and inhibitory receptors.•NK cell infiltration is a favorable prognostic factor in various solid tumors.•mAbs against inhibitory receptors ...enhance NK cell functions in vivo.
After many years of research, recent advances have shed new light on the role of the immune system in advanced-stage cancer. Various types of immune cells may be useful for therapeutic purposes, along with chemical molecules and engineered monoclonal antibodies. The immune effectors suitable for manipulation for adoptive transfer or drug targeting in vivo include natural killer (NK) cells. These cells are of particular interest because they are tightly regulated by an array of inhibitory and activating receptors, enabling them to kill tumor cells while sparing normal cells. New therapeutic antibodies blocking the interactions of inhibitory receptors (immune checkpoint inhibitors, ICI) with their ligands have been developed and can potentiate NK cell functions in vivo.
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