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J Autoimmun. 2020 Feb 5:102417. doi: 10.1016/j.jaut.2020.102417. [Epub ahead of print]

Innate inflammation drives NK cell activation to impair Treg activity.

Author information

1
Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Department of Infectious Disease and Immunology, University of Florida, Gainesville, FL, USA.
2
Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA.
3
Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; NanoString Technologies, Seattle, WA, USA.
4
Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; BD Biosciences, Ashland, OR, USA.
5
Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Fate Therapeutics, San Diego, CA, USA.
6
Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
7
Department of Pediatrics, University of Florida, Gainesville, FL, USA.
8
Department of Pediatrics, Emory University, Atlanta, GA, USA.
9
Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Department of Pediatrics, University of Florida, Gainesville, FL, USA.
10
Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Department of Pediatrics, University of Florida, Gainesville, FL, USA. Electronic address: tbrusko@ufl.edu.

Abstract

IL-12 and IL-18 synergize to promote TH1 responses and have been implicated as accelerators of autoimmune pathogenesis in type 1 diabetes (T1D). We investigated the influence of these cytokines on immune cells involved in human T1D progression: natural killer (NK) cells, regulatory T cells (Tregs), and cytotoxic T lymphocytes (CTL). NK cells from T1D patients exhibited higher surface CD226 versus controls and lower CD25 compared to first-degree relatives and controls. Changes in NK cell phenotype towards terminal differentiation were associated with cytomegalovirus (CMV) seropositivity, while possession of IL18RAP, IFIH1, and IL2RA T1D-risk variants impacted NK cell activation as evaluated by immuno-expression quantitative trait loci (eQTL) analyses. IL-12 and IL-18 stimulated NK cells from healthy donors exhibited enhanced specific killing of myelogenous K562 target cells. Moreover, activated NK cells increased expression of NKG2A, NKG2D, CD226, TIGIT and CD25, which enabled competition for IL-2 upon co-culture with Tregs, resulting in Treg downregulation of FOXP3, production of IFNγ, and loss of suppressive function. We generated islet-autoreactive CTL "avatars", which upon exposure to IL-12 and IL-18, upregulated IFNγ and Granzyme-B leading to increased lymphocytotoxicity of a human β-cell line in vitro. These results support a model for T1D pathogenesis wherein IL-12 and IL-18 synergistically enhance CTL and NK cell cytotoxic activity and disrupt immunoregulation by Tregs.

KEYWORDS:

IL-12; IL-18; Immunoregulation; NK cells; Regulatory T cells; Type 1 diabetes

PMID:
32035746
DOI:
10.1016/j.jaut.2020.102417

Conflict of interest statement

Declaration of competing interest The authors declare that no conflicts of interest exist pertaining to the work reported herein.

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