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IL-15 Generates IFN-?-producing Cells Reciprocally Expressing Lymphoid-Myeloid Markers during Dendritic Cell Differentiation.

ABSTRACT: Recently, interest in IL-15-differentiated cells has increased; however, the phenotypic definition of IL-15-differentiated bone marrow-derived cells (IL-15-DBMCs) is still under debate, particularly the generation of IFN-?-producing innate cells such as premature NK (pre-mNK) cells, natural killer dendritic cells (NKDCs), interferon-producing killer dendritic cells (IKDCs), and type 1 innate lymphoid cells (ILC1s), all of which are IL-15-dependent. Here, we revisited the immunophenotypic characteristics of IFN-?-producing IL-15-DBMCs and their functional role in the control of intracellular Mycobacterium tuberculosis (Mtb) infection. When comparing the cytokine levels between bone marrow-derived dendritic cells (BMDCs) and IL-15-DBMCs upon stimulation with various TLR agonists, only the CD11c^int population of IL-15-DBMCs produced significant levels of IFN-?, decreased levels of MHC-II, and increased levels of B220. Neither BMDCs nor IL-15-DBMCs were found to express DX5 or NK1.1, which are representative markers for the NK cell lineage and IKDCs. When the CD11c^intB220⁺ population of IL-15-DBMCs was enriched, the Thy1.2⁺Sca-1⁺ population showed a marked increase in IFN-? production. In addition, while depletion of the B220⁺ and Thy1.2⁺ populations of IL-15-DBMCs, but not the CD19⁺ population, inhibited IFN-? production, enrichment of these cell populations increased IFN-?. Ultimately, co-culture of sorted IFN-?-producing B220⁺Thy1.2⁺ IL-15-DBMCs with Mtb-infected macrophages resulted in control of the intracellular growth of Mtb via the IFN-?-nitric oxide axis in a donor cell number-dependent manner. Taken together, the results indicate that IFN-?-producing IL-15-DBMCs could be redefined as CD11c^intB220⁺Thy1.2⁺Sca-1⁺ cells, which phenotypically resemble both IKDCs and ILC1s, and may have therapeutic potential for controlling infectious intracellular bacteria such as Mtb.

SUBMITTER: Kwon KW

PROVIDER: S-EPMC6367559 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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IL-15 Generates IFN-γ-producing Cells Reciprocally Expressing Lymphoid-Myeloid Markers during Dendritic Cell Differentiation.

Kwon Kee Woong KW Kim So Jeong SJ Kim Hongmin H Kim Woo Sik WS Kang Soon Myung SM Choi Eunsol E Ha Sang-Jun SJ Yoon Joo-Heon JH Shin Sung Jae SJ

International journal of biological sciences 20190101 2

Recently, interest in IL-15-differentiated cells has increased; however, the phenotypic definition of IL-15-differentiated bone marrow-derived cells (IL-15-DBMCs) is still under debate, particularly the generation of IFN-γ-producing innate cells such as premature NK (pre-mNK) cells, natural killer dendritic cells (NKDCs), interferon-producing killer dendritic cells (IKDCs), and type 1 innate lymphoid cells (ILC1s), all of which are IL-15-dependent. Here, we revisited the immunophenotypic charact ...[more]

PMID: 30745835

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Project description:We have shown that manipulation of IL-13 and STAT6 signaling at the vaccination site can lead to different innate lymphoid cell (ILC)/dendritic cell (DC) recruitment, resulting in high avidity/poly-functional T cells and effective antibody differentiation. Here we show that permanent versus transient blockage of IL-13 and STAT6 at the vaccination site can lead to unique ILC-derived IL-13 and IFN-γ profiles, and differential IL-13Rα2, type I and II IL-4 receptor regulation on ILC. Specifically, STAT6-/- BALB/c mice given fowl pox virus (FPV) expressing HIV antigens induced elevated ST2/IL-33R+ ILC2-derived IL-13 and reduced NKp46+/- ILC1/ILC3-derived IFN-γ expression, whilst the opposite (reduced IL-13 and elevated IFN-γ expression) was observed during transient inhibition of STAT6 signaling in wild type BALB/c mice given FPV-HIV-IL-4R antagonist vaccination. Interestingly, disruption/inhibition of STAT6 signaling considerably impacted IL-13Rα2 expression by ST2/IL-33R+ ILC2 and NKp46- ILC1/ILC3, unlike direct IL-13 inhibition. Consistently with our previous findings, this further indicated that inhibition of STAT6 most likely promoted IL-13 regulation via IL-13Rα2. Moreover, the elevated ST2/IL-33R+ IL-13Rα2+ lung ILC2, 24 h post FPV-HIV-IL-4R antagonist vaccination was also suggestive of an autocrine regulation of ILC2-derived IL-13 and IL-13Rα2, under certain conditions. Knowing that IL-13 can modulate IFN-γ expression, the elevated expression of IFN-γR on lung ST2/IL-33R+ ILC2 provoked the notion that there could also be inter-regulation of lung ILC2-derived IL-13 and NKp46- ILC1/ILC3-derived IFN-γ via their respective receptors (IFN-γR and IL-13Rα2) at the lung mucosae early stages of vaccination. Intriguingly, under different IL-13 conditions differential regulation of IL-13/IL-13Rα2 on lung DC was also observed. Collectively these findings further substantiated that IL-13 is the master regulator of, not only DC, but also different ILC subsets at early stages of viral vector vaccination, and responsible for shaping the downstream adaptive immune outcomes. Thus, thoughtful selection of vaccine strategies/adjuvants that can manipulate IL-13Rα2, and STAT6 signaling at the ILC/DC level may prove useful in designing more efficacious vaccines against different/chronic pathogens.

Dataset Information

IL-15 Generates IFN-?-producing Cells Reciprocally Expressing Lymphoid-Myeloid Markers during Dendritic Cell Differentiation.

Publications

IL-15 Generates IFN-γ-producing Cells Reciprocally Expressing Lymphoid-Myeloid Markers during Dendritic Cell Differentiation.

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