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IL-10-producing Th1 cells and disease progression are regulated by distinct CD11c⁺ cell populations during visceral leishmaniasis.

ABSTRACT: IL-10 is a critical regulatory cytokine involved in the pathogenesis of visceral leishmaniasis caused by Leishmania donovani and clinical and experimental data indicate that disease progression is associated with expanded numbers of CD4⁺ IFNγ⁺ T cells committed to IL-10 production. Here, combining conditional cell-specific depletion with adoptive transfer, we demonstrate that only conventional CD11c(hi) DCs that produce both IL-10 and IL-27 are capable of inducing IL-10-producing Th1 cells in vivo. In contrast, CD11c(hi) as well as CD11c(int/lo) cells isolated from infected mice were capable of reversing the host protective effect of diphtheria toxin-mediated CD11c⁺ cell depletion. This was reflected by increased splenomegaly, inhibition of NO production and increased parasite burden. Thus during chronic infection, multiple CD11c⁺ cell populations can actively suppress host resistance and enhance immunopathology, through mechanisms that do not necessarily involve IL-10-producing Th1 cells.

SUBMITTER: Owens BM

PROVIDER: S-EPMC3406093 | biostudies-literature |

REPOSITORIES: biostudies-literature

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IL-10-producing Th1 cells possess a distinct molecular signature in malaria

Project description:Control of intracellular parasites responsible for malaria requires host IFN-γ+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10-producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10-Th1 cells from IL-10+Tr1 cells in Plasmodium falciparum-infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human CD4+ T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human CD4+ T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into CD4+ T cell development during malaria that offer opportunities for creation of strategies to modulate CD4+ T cell functions and improve antiparasitic immunity.

| S-EPMC9797345 | biostudies-literature

Targeting IL-27 and/or IL-10 in Experimental Murine Visceral Leishmaniasis.

Project description:Interleukin-10 (IL-10) and interleukin-27 (IL-27) both exert counterregulatory immunodeactivation in visceral Leishmania donovani infection. We studied experimental L. donovani infection in the livers of IL-10-/- and IL-27Rα-/- mice and observed that in IL-27Rα-/-, but not IL-10-/- mice, interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) were required for heightened granulomatous inflammation and accelerated control of intracellular parasite replication. This difference in mechanism, along with residual IL-10 activity in IL-27Rα-/- mice, suggested targeting IL-27 in addition to IL-10 in a macrophage-activating, anti-counterregulatory cytokine treatment strategy. In C57BL/6 wild-type mice with established liver infection, a single injection of anti-IL-27 p28 or anti-IL-10R monoclonal antibody enhanced granuloma assembly, enabled macrophage activation, and induced comparable parasite killing (49-56%). However, anti-IL-27 p28 plus anti-IL-10R combination treatment did not increase leishmanicidal effects. These results suggest that IL-27 and IL-10 may operate in a linked deactivating mechanism and that in this intracellular infection, either IL-27 or IL-10 is a suitable immunotherapeutic target.

| S-EPMC7646755 | biostudies-literature

IL-3 and CSF-1 interact to promote generation of CD11c+ IL-10-producing macrophages.

Project description:Unraveling the mechanisms of hematopoiesis regulated by multiple cytokines remains a challenge in hematology. IL-3 is an allergic cytokine with the multilineage potential, while CSF-1 is produced in the steady state with restricted lineage coverage. Here, we uncovered an instructive role of CSF-1 in IL-3-mediated hematopoiesis. CSF-1 significantly promoted IL-3-driven CD11c+ cell expansion and dampened basophil and mast cell generation from C57BL/6 bone marrow. Further studies indicated that the CSF-1/CSF-1R axis contributed significantly to IL-3-induced CD11c+ cell generation through enhancing c-Fos-associated monopoiesis. CD11c+ cells induced by IL-3 or IL-3/CSF-1 were competent in cellular maturation and endocytosis. Both IL-3 and IL-3/CSF-1 cells lacked classical dendritic cell appearance and resembled macrophages in morphology. Both populations produced a high level of IL-10, in addition to IL-1, IL-6 and TNF?, in response to LPS, and were relatively poor T cell stimulators. Collectively, these findings reveal a role for CSF-1 in mediating the IL-3 hematopoietic pathway through monopoiesis, which regulates expansion of CD11c+ macrophages.

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Is the polymorphism at position -1082 of IL-10 gene associated with visceral leishmaniasis?

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| S-EPMC4411907 | biostudies-other

Mycobacterium tuberculosis Mannose-Capped Lipoarabinomannan Induces IL-10-Producing B Cells and Hinders CD4+Th1 Immunity.

Project description:The importance of Th1/interferon (IFN)-?-mediated responses in mycobacterial infection has been well established. However, little is known about B cell-mediated immunity during Mycobacterium tuberculosis (Mtb) infection. Interleukin (IL)-10-producing B cells (B10 cells), a subset of B regulatory cells (Bregs), are implicated in modulating the immune response. Herein, we found that B10 cells were significantly increased in patients with tuberculosis. Furthermore, mannose-capped lipoarabinomannan (ManLAM), a major surface lipoglycan component from Mtb, induced a significant increase in B10 cells, which enriched in CD5+ B1a B cells. ManLAM induced IL-10 production mainly by activating MyD88/PI3K/AKT/Ap-1 and K63-linked ubiquitination of NF-?B essential modulator/nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathways in B cells via Toll-like receptor 2. IL-10 production by ManLAM-treated B cells further inhibited CD4+ Th1 polarization, leading to increased susceptibility to mycobacterial infection compared with ManLAM-treated IL-10-/- B group. Thus, we report a new immunoregulation mechanism in which Mtb ManLAM-induced B10 cells negatively regulate host anti-TB cellular immunity.

| S-EPMC6299163 | biostudies-literature

CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis.

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| S-EPMC2118728 | biostudies-literature

IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation.

Project description:IL-10 is an immunomodulatory cytokine with a critical role in limiting inflammation in immune-mediated pathologies. The mechanisms leading to IL-10 expression by CD4+ T cells are being elucidated, with several cytokines implicated. We explored the effect of IL-4 on the natural phenomenon of IL-10 production by a chronically stimulated antigen-specific population of differentiated Th1 cells. In vitro, IL-4 blockade inhibited while addition of exogenous IL-4 to Th1 cultures enhanced IL-10 production. In the in vivo setting of peptide immunotherapy leading to a chronically stimulated Th1 phenotype, lack of IL-4Rα inhibited the induction of IL-10. Exploring the interplay of Th1 and Th2 cells through co-culture, Th2-derived IL-4 promoted IL-10 expression by Th1 cultures, reducing their pathogenicity in vivo. Co-culture led to upregulated c-Maf expression with no decrease in the proportion of T-bet+ cells in these cultures. Addition of IL-4 also reduced the encephalitogenic capacity of Th1 cultures. These data demonstrate that IL-4 contributes to IL-10 production and that Th2 cells modulate Th1 cultures towards a self-regulatory phenotype, contributing to the cross-regulation of Th1 and Th2 cells. These findings are important in the context of Th1 driven diseases since they reveal how the Th1 phenotype and function can be modulated by IL-4.

| S-EPMC5595963 | biostudies-literature

Regulatory IgDhi B Cells Suppress T Cell Function via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis.

Project description:During visceral leishmaniasis (VL), Th1-based inflammation is induced to control intracellular parasites. Inflammation-based pathology was shown to be dampened by IL-10 and eventual programmed death 1-mediated T cell exhaustion. Cell type(s) responsible for the initiation of T cell-produced IL-10 during VL are unknown. CD19(+), CD5(-), CD1d(-), IgD(hi) regulatory B cells from healthy controls produced IL-10 in the absence of infection or stimulation, in contrast to IgD(lo/neg) B cells. IgD(hi) B cells may have a de novo versus induced regulatory program. The population of IgD(hi) B cells increased 3-fold as VL progressed. B cells from VL dogs were necessary and sufficient to suppress Th1 cell effector function. IgD(hi) B cells induced IL-10 production by T cells and IgD(lo) B cells. Blockage of B cell-specific PD-L1 restored Th1 responses. IgD(hi) regulatory B cells represent a novel regulatory B cell that may precipitate T cell exhaustion during VL.

| S-EPMC4868652 | biostudies-literature

IL-10-producing NKT10 cells are a distinct regulatory invariant NKT cell subset.

Project description:Invariant natural killer T (iNKT) cells rapidly produce copious amounts of multiple cytokines after activation, thereby impacting a wide variety of different immune reactions. However, strong activation of iNKT cells with α-galactosylceramide (αGalCer) reportedly induces a hyporeactive state that resembles anergy. In contrast, we determined here that iNKT cells from mice pretreated with αGalCer retain cytotoxic activity and maintain the ability to respond to TCR-dependent as well as TCR-independent cytokine-mediated stimulation. Additionally, αGalCer-pretreated iNKT cells acquired characteristics of regulatory cells, including production and secretion of the immunomodulatory cytokine IL-10. Through the production of IL-10, αGalCer-pretreated iNKT cells impaired antitumor responses and reduced disease in experimental autoimmune encephalomyelitis, a mouse model of autoimmune disease. Furthermore, a subset of iNKT cells with a similar inhibitory phenotype and function were present in mice not exposed to αGalCer and were enriched in mouse adipose tissue and detectable in human PBMCs. These data demonstrate that IL-10-producing iNKT cells with regulatory potential (NKT10 cells) represent a distinct iNKT cell subset.

| S-EPMC4151203 | biostudies-literature

HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis.

Project description:Inflammation, although responsible for controlling infection, is often associated with the pathogenesis of chronic diseases. Leishmania donovani, the causative agent of visceral leishmaniasis, induces a strong inflammatory response that leads to splenomegaly and ultimately immune suppression. Inflamed tissues are typically characterized by low levels of oxygen, a microenvironment that triggers the hypoxia-inducible transcription factor 1α (HIF-1α). Although HIF-1α plays an integral role in dendritic cell function, its involvement in the generation of protective Th1 responses against Leishmania has not yet been studied. Here we demonstrate that HIF-1α inhibits IL-12 production in dendritic cells, limiting therefore Th1 cell development. Indeed, depletion of HIF-1α in CD11c+ cells resulted in higher and sustained expression of IL-12 and complete abrogation of IL-10. Moreover, CD11c-specific HIF-1α-deficient mice showed higher frequencies of IFN-γ-producing CD4 T cells in the spleen and bone marrow and, consequently, a significantly reduced parasite burden in both organs. Taken together, our results suggest that HIF-1α expression in dendritic cells largely contributes to the establishment of persistent Leishmania infection and may therefore represent a possible therapeutic target.

| S-EPMC5823892 | biostudies-literature

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