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MICa/b-dependent activation of natural killer cells by CD64⁺ inflammatory type 2 dendritic cells contributes to autoimmunity.

ABSTRACT: Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune disorder largely mediated by type I and II interferon (IFN). The potential contribution of innate immune cells, such as natural killer (NK) cells and dendritic cells (DC), to the pSS pathology remains understudied. Here, we identified an enriched CD16⁺ CD56hi NK cell subset associated with higher cytotoxic function, as well as elevated proportions of inflammatory CD64⁺ conventional dendritic cell (cDC2) subtype that expresses increased levels of MICa/b, the ligand for the activating receptor NKG2D, in pSS individuals. Circulating cDC2 from pSS patients efficiently induced activation of cytotoxic NK cells ex vivo and were found in proximity to CD56⁺ NK cells in salivary glands (SG) from pSS patients. Interestingly, transcriptional activation of IFN signatures associated with the RIG-I/DDX60 pathway, IFN I receptor, and its target genes regulate the expression of NKG2D ligands on cDC2 from pSS patients. Finally, increased proportions of CD64hi RAE-1⁺ cDC2 and NKG2D⁺ CD11b⁺ CD27⁺ NK cells were present in vivo in the SG after poly I:C injection. Our study provides novel insight into the contribution and interplay of NK and cDC2 in pSS pathology and identifies new potential therapy targets.

SUBMITTER: Sanchez-Cerrillo I

PROVIDER: S-EPMC10690448 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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MICa/b-dependent activation of natural killer cells by CD64+ inflammatory type 2 dendritic cells contributes to autoimmunity.

Sánchez-Cerrillo Ildefonso I Calzada-Fraile Diego D Triguero-Martínez Ana A Calvet-Mirabent Marta M Popova Olga O Delgado-Arévalo Cristina C Valdivia-Mazeyra Mariel M Ramírez-Huesca Marta M de Luis Enrique Vázquez EV Benguría Alberto A Aceña-Gonzalo Teresa T Moreno-Vellisca Roberto R de Llano Magdalena Adrados MA de la Fuente Hortensia H Tsukalov Ilya I Delgado-Wicke Pablo P Fernández-Ruiz Elena E Roy-Vallejo Emilia E Tejedor-Lázaro Reyes R Ramiro Almudena A Iborra Salvador S Sánchez-Madrid Francisco F Dopazo Ana A Álvaro Isidoro González IG Castañeda Santos S Martin-Gayo Enrique E

The EMBO journal 20231102 23

Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune disorder largely mediated by type I and II interferon (IFN). The potential contribution of innate immune cells, such as natural killer (NK) cells and dendritic cells (DC), to the pSS pathology remains understudied. Here, we identified an enriched CD16+ CD56hi NK cell subset associated with higher cytotoxic function, as well as elevated proportions of inflammatory CD64+ conventional dendritic cell (cDC2) subtype ...[more]

PMID: 37916875

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Project description:UnlabelledThe initiating events in autoimmune disease remain to be completely understood, but it is thought that genetic predisposition synergizes with "environmental" factors, including viral infection, leading to disease. One elegant animal model used to study the pathogenesis of multiple sclerosis that perfectly blends genetics and environmental components in the context of virus-induced autoimmunity is Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD). TMEV-infected disease-susceptible SJL/J mice develop a persistent central nervous system (CNS) infection and later develop autoimmune demyelination, while disease-resistant C57BL/6 (B6) mice rapidly clear the infection and develop no autoimmune pathology. Mice of the (B6 × SJL/J)F1 cross between these two mouse strains are classified as intermediately susceptible. We employed this model to investigate if rapid virus clearance in B6 versus SJL/J mice was perhaps related to differences in the innate immune response in the CNS of the two strains in the first few days following intracerebral virus inoculation. Here we show that SJL/J mice lack, in addition to NK cells, a novel innate immune subset known as natural killer dendritic cells (NKDCs), which express phenotypic markers (CD11c(int) NK1.1(+)) and functional activity of both NK cells and DCs. These NKDCs are activated in the periphery and migrate into the infected CNS in a very late antigen 4 (VLA-4)-dependent fashion. Most significantly, NKDCs are critical for CNS clearance of TMEV, as transfer of NKDCs purified from B6 mice into TMEV-IDD-susceptible (B6 × SJL/J)F1 mice promotes viral clearance. Together the findings of this work show for the first time a link between NKDCs, viral infection, and CNS autoimmunity.ImportanceViral infection is an important cofactor, along with genetic susceptibility, in the initiation of a variety of organ-specific autoimmune diseases. Thus, in-depth understanding of how virus infections trigger autoimmunity may lead to novel ways to prevent or treat these diseases. Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD) serves as an important model for the human T cell-mediated autoimmune demyelinating disease multiple sclerosis. Induction of TMEV-IDD is genetically controlled as SJL/J mice develop persistent central nervous system (CNS) infection leading to chronic autoimmune demyelination, while C57BL/6 mice rapidly clear virus and are disease resistant. We determined that, as opposed to resistant B6 mice, disease-susceptible SJL/J mice lacked a unique innate immune population, the natural killer dendritic cell (NKDC), which was shown to play a critical role in early CNS virus clearance via its ability to both present virus antigen to T cells and to lyse target cells.

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MICa/b-dependent activation of natural killer cells by CD64⁺ inflammatory type 2 dendritic cells contributes to autoimmunity.

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MICa/b-dependent activation of natural killer cells by CD64<sup>+</sup> inflammatory type 2 dendritic cells contributes to autoimmunity.

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