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Interferon-γ-Producing CD4⁺ T Cells Drive Monocyte Activation in the Bone Marrow During Experimental Leishmania donovani Infection.

ABSTRACT: Ly6C^hi inflammatory monocytes develop in the bone marrow and migrate to the site of infection during inflammation. Upon recruitment, Ly6C^hi 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 Ly6C^hi 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 Ly6C^hi monocytes increased over time. Ly6C^hi 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, Ly6C^hi 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.

SUBMITTER: Romano A

PROVIDER: S-EPMC8453021 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In leishmaniasis, the protective immunity is largely mediated by proinflammatory cytokine producing abilities of T cells and an efficient parasite killing by phagocytic cells. Notwithstanding a substantial progress that has been made during last decades, the mechanisms or factors involved in establishing protective immunity against Leishmania are not identified. In ancient Indian literature, metallic "bhasma," particularly that of "swarna" or gold (fine gold particles), is indicated as one of the most prominent metal-based therapeutic medicine, which is known to impart protective and curative properties in various health issues. In this work, we elucidated the potential of swarna bhasma (SB) on the effector properties of phagocytes and antigen-activated CD4+ T cells in augmenting the immunogenicity of L. donovani antigens. The characterization of SB revealing its shape, size, composition, and measurement of cytotoxicity established the physiochemical potential for its utilization as an immunomodulator. The activation of macrophages with SB enhanced their capacity to produce nitric oxide and proinflammatory cytokines, which eventually resulted in reduced uptake of parasites and their proliferation in infected cells. Further, in Leishmania-infected animals, SB administration reduced the generation of IL-10, an anti-inflammatory cytokine, and enhanced pro-inflammatory cytokine generation by antigen activated CD4+ T cells with increased frequency of double (IFNγ+/TNFα+) and triple (IFNγ+TNFα+IL-2+) positive cells and abrogated disease pathogeneses at the early days of infection. Our results also suggested that cow-ghee (A2) emulsified preparation of SB, either alone or with yashtimadhu, a known natural immune modulator which enhances the SB's potential in enhancing the immunogenicity of parasitic antigens. These findings suggested a definite potential of SB in enhancing the effector functions of phagocytes and CD4+ T cells against L. donovani antigens. Therefore, more studies are needed to elucidate the mechanistic details of SB and its potential in enhancing vaccine-induced immunity.

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.

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Interferon-γ-Producing CD4⁺ T Cells Drive Monocyte Activation in the Bone Marrow During Experimental Leishmania donovani Infection.

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Interferon-γ-Producing CD4+ T Cells Drive Monocyte Activation in the Bone Marrow During Experimental Leishmania donovani Infection.

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OmicsDI is part of the ELIXIR infrastructure

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Interferon-γ-Producing CD4⁺ T Cells Drive Monocyte Activation in the Bone Marrow During Experimental Leishmania donovani Infection.