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Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis.

ABSTRACT: Atopic dermatitis (AD) is a widespread, chronic skin disease associated with aberrant allergic inflammation. Current treatments involve either broad or targeted immunosuppression strategies. However, enhancing the immune system to control disease remains untested. We demonstrate that patients with AD harbor a blood natural killer (NK) cell deficiency that both has diagnostic value and improves with therapy. Multidimensional protein and RNA profiling revealed subset-level changes associated with enhanced NK cell death. Murine NK cell deficiency was associated with enhanced type 2 inflammation in the skin, suggesting that NK cells play a critical immunoregulatory role in this context. On the basis of these findings, we used an NK cell-boosting interleukin-15 (IL-15) superagonist and observed marked improvement in AD-like disease in mice. These findings reveal a previously unrecognized application of IL-15 superagonism, currently in development for cancer immunotherapy, as an immunotherapeutic strategy for AD.

SUBMITTER: Mack MR

PROVIDER: S-EPMC7433875 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis.

Mack Madison R MR Brestoff Jonathan R JR Berrien-Elliott Melissa M MM Trier Anna M AM Yang Ting-Lin B TB McCullen Matthew M Collins Patrick L PL Niu Haixia H Bodet Nancy D ND Wagner Julia A JA Park Eugene E Xu Amy Z AZ Wang Fang F Chibnall Rebecca R Council M Laurin ML Heffington Carrie C Kreisel Friederike F Margolis David J DJ Sheinbein David D Lovato Paola P Vivier Eric E Cella Marina M Colonna Marco M Yokoyama Wayne M WM Oltz Eugene M EM Fehniger Todd A TA Kim Brian S BS

Science translational medicine 20200201 532

Atopic dermatitis (AD) is a widespread, chronic skin disease associated with aberrant allergic inflammation. Current treatments involve either broad or targeted immunosuppression strategies. However, enhancing the immune system to control disease remains untested. We demonstrate that patients with AD harbor a blood natural killer (NK) cell deficiency that both has diagnostic value and improves with therapy. Multidimensional protein and RNA profiling revealed subset-level changes associated with ...[more]

PMID: 32102931

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Project description:BackgroundTuberculosis (TB) continues to be a critical global health problem, which killed millions of lives each year. Certain circulating cell subsets are thought to differentially modulate the host immune response towards Mycobacterium tuberculosis (Mtb) infection, but the nature and function of these subsets is unclear.MethodsPeripheral blood mononuclear cells (PBMC) were isolated from healthy controls (HC), latent tuberculosis infection (LTBI) and active tuberculosis (TB) and then subjected to single-cell RNA sequencing (scRNA-seq) using 10?×?Genomics platform. Unsupervised clustering of the cells based on the gene expression profiles using the Seurat package and passed to tSNE for clustering visualization. Flow cytometry was used to validate the subsets identified by scRNA-Seq.FindingsCluster analysis based on differential gene expression revealed both known and novel markers for all main PBMC cell types and delineated 29 cell subsets. By comparing the scRNA-seq datasets from HC, LTBI and TB, we found that infection changes the frequency of immune-cell subsets in TB. Specifically, we observed gradual depletion of a natural killer (NK) cell subset (CD3-CD7+GZMB+) from HC, to LTBI and TB. We further verified that the depletion of CD3-CD7+GZMB+ subset in TB and found an increase in this subset frequency after anti-TB treatment. Finally, we confirmed that changes in this subset frequency can distinguish patients with TB from LTBI and HC.InterpretationWe propose that the frequency of CD3-CD7+GZMB+ in peripheral blood could be used as a novel biomarker for distinguishing TB from LTBI and HC. FUND: The study was supported by Natural Science Foundation of China (81770013, 81525016, 81772145, 81871255 and 91942315), National Science and Technology Major Project (2017ZX10201301), Science and Technology Project of Shenzhen (JCYJ20170412101048337) and Guangdong Provincial Key Laboratory of Regional Immunity and Diseases (2019B030301009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Dataset Information

Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis.

Publications

Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis.

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