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Interferon-? Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4⁺ T Cells in Chronic Lymphopenic Mice.

ABSTRACT: In lymphopenic mice, T cells become activated and undergo lymphopenia-induced proliferation (LIP). However, not all T cells are equally sensitive to lymphopenia. Several lymphopenia-insensitive T cell clones were described and their non-responsiveness was mainly attributed to clone-specific properties. Here, we provide evidence for an additional, host-dependent mechanism restraining LIP of lymphopenia-insensitive CD4⁺ T cells. We show that such cells undergo LIP in lymphopenic mice lacking IFN-? receptor (IFN-?R) expression, a process, which is promoted by the autocrine action of T cell-derived IFN-?. Additionally, LIP of lymphopenia-insensitive CD4⁺ T cells requires an intact microflora and is accompanied by the massive accumulation of IL-6 and dendritic cells (DCs). Consistent with these results, IL-6 neutralization and the DC-specific restoration of IFN-?R expression are both sufficient to restrict LIP. Hence, the insensitivity of CD4⁺ T cells to lymphopenia relies on cell-intrinsic properties and a complex interplay between the commensal microflora, IL-6, IFN-?R⁺ DCs, and T cell-derived IFN-?.

SUBMITTER: Knop L

PROVIDER: S-EPMC6374634 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Interferon-γ Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4<sup>+</sup> T Cells in Chronic Lymphopenic Mice.

Knop Laura L Frommer Charlotte C Stoycheva Diana D Deiser Katrin K Kalinke Ulrich U Blankenstein Thomas T Kammertoens Thomas T Dunay Ildiko Rita IR Schüler Thomas T

Frontiers in immunology 20190207

In lymphopenic mice, T cells become activated and undergo lymphopenia-induced proliferation (LIP). However, not all T cells are equally sensitive to lymphopenia. Several lymphopenia-insensitive T cell clones were described and their non-responsiveness was mainly attributed to clone-specific properties. Here, we provide evidence for an additional, host-dependent mechanism restraining LIP of lymphopenia-insensitive CD4<sup>+</sup> T cells. We show that such cells undergo LIP in lymphopenic mice la ...[more]

PMID: 30792713

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Project description:IntroductionMitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown.ObjectivesWe investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model.MethodsWe induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry.ResultsSpred2-deficient mice (Spred2-/-) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2-/- mice, and pretreatment of Spred2-/- mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2-/- mice. IFNγ was mainly produced from CD4+ and CD8+ T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4+ and/or CD8+ T cells from Spred2-/- mice into RAG1-/- mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2-/- mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4+ and CD8+ T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4+ and CD8+ T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A in vitro.ConclusionWe demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.

Project description:Ly6Chi inflammatory monocytes develop in the bone marrow and migrate to the site of infection during inflammation. Upon recruitment, Ly6Chi monocytes can differentiate into dendritic cells or macrophages. According to the tissue environment they can also acquire different functions. Several studies have described pre-activation of Ly6Chi monocytes in the bone marrow during parasitic infection, but whether this process occurs during experimental visceral leishmaniasis and, if so, the mechanisms contributing to their activation are yet to be established. In wild type C57BL/6 (B6) mice infected with Leishmania donovani, the number of bone marrow Ly6Chi monocytes increased over time. Ly6Chi monocytes displayed a highly activated phenotype from 28 days to 5 months post infection (p.i), with >90% expressing MHCII and >20% expressing iNOS. In comparison, in B6.Rag2 -/- mice <10% of bone marrow monocytes were MHCII+ at day 28 p.i., an activation deficiency that was reversed by adoptive transfer of CD4+ T cells. Depletion of CD4+ T cells in B6 mice and the use of mixed bone marrow chimeras further indicated that monocyte activation was driven by IFNγ produced by CD4+ T cells. In B6.Il10 -/- mice, L. donovani infection induced a faster but transient activation of bone marrow monocytes, which correlated with the magnitude of CD4+ T cell production of IFNγ and resolution of the infection. Under all of the above conditions, monocyte activation was associated with greater control of parasite load in the bone marrow. Through reinfection studies in B6.Il10 -/- mice and drug (AmBisome®) treatment of B6 mice, we also show the dependence of monocyte activation on parasite load. In summary, these data demonstrate that during L. donovani infection, Ly6Chi monocytes are primed in the bone marrow in a process driven by CD4+ T cells and whereby IFNγ promotes and IL-10 limits monocyte activation and that the presence of parasites/parasite antigen plays a crucial role in maintaining bone marrow monocyte activation.

Dataset Information

Interferon-? Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4⁺ T Cells in Chronic Lymphopenic Mice.

Publications

Interferon-γ Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4<sup>+</sup> T Cells in Chronic Lymphopenic Mice.

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Dataset Information

Interferon-? Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4+ T Cells in Chronic Lymphopenic Mice.

Publications

Interferon-γ Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4<sup>+</sup> T Cells in Chronic Lymphopenic Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Interferon-? Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4⁺ T Cells in Chronic Lymphopenic Mice.