Priming Of Th1 Cells Research Articles

Disease-specific T-helper cell polarizing function of lesional dendritic cells in different types of chronic rhinosinusitis with nasal polyps.

Although eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) exhibit distinct T-helper (Th) responses, the underlying mechanisms remain unclear. To clarify the phenotypes and Th-cell polarizing functions of dendritic cells (DCs) in different types of CRSwNP. DC subsets, their surface phenotypes, and Th-cell subsets were studied by means of immunohistochemistry and flow cytometry. The sorted lesional DCs were activated or cultured with autologous naive CD4(+) T cells, and cytokine production was determined by ELISA. Thymic stromal lymphopoietin and osteopontin expression were detected by means of reverse-transcriptase polymerase chain reaction. Although elevated local Th1 and Th17 cells were noted in both eosinophilic and noneosinophilic CRSwNP, increased Th2 cells were found only in eosinophilic CRSwNP. Increased numbers of myeloid DCs, plasmacytoid DCs, and their activated subsets were found in both types of CRSwNP, but only myeloid DCs and plasmacytoid DCs from eosinophilic CRSwNP demonstrated an up-regulation of OX40 ligand (OX40L) and programmed death ligand 1(PD-L1) expression. Lesional DCs from both types of CRSwNP produced enhanced levels of IL-12, IL-6, and transforming growth factor-β, and induced increased Th1 and Th17 responses; in contrast, only DCs from eosinophilic CRSwNP induced obviously enhanced Th2 responses, when cocultured with naive CD4(+) T cells. Blockade of OX40L and PD-L1 on lesional DCs from eosinophilic CRSwNP suppressed Th2 responses, but promoted Th1 responses in DC-T cell coculture. Distinct subsets of lesional DCs were found in eosinophilic and noneosinophilic CRSwNP, where OX40L/PD-L1(+) lesional DCs in eosinophilic CRSwNP could prime Th2 cells, whereas the low OX40L/PD-L1-expressing lesional DCs in noneosinophilic CRSwNP primarily induced Th1/Th17 cells.

TSLP signaling in CD4 T cells is required for T helper 2 memory (HYP6P.259)

Abstract Thymic stromal lymphopoietin (TSLP) plays important roles in the differentiation of T helper 2 (Th2) cells and thus the pathogenesis of allergic diseases. Whether TSLP is required for the generation and maintenance of Th2 memory cells has not been clearly defined. In this study, we show that TSLP signaling in CD4 T cells is required for the generation of memory cells following OVA+Alum priming. TSLPR-deficient CD4 T cells have no defects in proliferation but fail to survive one week after sensitization, while elevated TSLP expression during sensitization significantly increased the frequency of memory cells. Although in vitro differentiated TSLPR-deficient Th2 cells develop into memory cells with equal efficiency to wild type cells, the recall response to airway antigen challenge is impaired. Moreover, after antigen challenge of mice receiving in vitro primed Th2 cells, TSLP signaling in CD4 T cells significantly affects memory cell generation from the secondary effector cells. Therefore, TSLP plays a critical role not only in Th2 memory generation in vivo, but also in recall response of the memory cells to local antigen challenge.

Regulation of experimental autoimmune encephalomyelitis by TPL-2 kinase.

Tumor progression locus 2 (TPL-2) expression is required for efficient polarization of naive T cells to Th1 effector cells in vitro, as well as for Th1-mediated immune responses. In the present study, we investigated the potential role of TPL-2 in Th17 cells. TPL-2 was found to be dispensable for Th17 cell differentiation in vitro, and for the initial priming of Th17 cells in experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated disease model for multiple sclerosis. Nevertheless, TPL-2-deficient mice were protected from EAE, which correlated with reduced immune cell infiltration, demyelination, and axonal damage in the CNS. Adoptive transfer experiments demonstrated that there was no T cell-intrinsic function for TPL-2 in EAE, and that TPL-2 signaling was not required in radiation-sensitive hematopoietic cells. Rather, TPL-2 signaling in radiation-resistant stromal cells promoted the effector phase of the disease. Importantly, using a newly generated mouse strain expressing a kinase-inactive form of TPL-2, we demonstrated that stimulation of EAE was dependent on the catalytic activity of TPL-2 and not its adaptor function to stabilize the associated ubiquitin-binding protein ABIN-2. Our data therefore raise the possibility that small molecule inhibitors of TPL-2 may be beneficial in multiple sclerosis therapy.

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

The immune mechanisms underlying delayed induction of Th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate Th1-type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen-bearing DCs to the draining lymph node (dLN), the Th1-cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1-type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1-cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1-type immunity against pulmonary mycobacterial diseases.

Delineating the Role of Histamine-1- and -4-Receptors in a Mouse Model of Th2-Dependent Antigen-Specific Skin Inflammation

BackgroundHistamine drives pruritus in allergic skin diseases which clinically constitutes a most disruptive symptom. Skin pathology in allergic skin diseases is crucially influenced by different T-helper subsets. However, the contribution of different histamine-receptors to T-helper cell dependent skin pathology has not been definitively answered. Models which can specifically address the functional role of T-helper subsets and the mediators involved are therefore valuable to gain further insights into molecular pathways which contribute to allergic skin disease. They might also be helpful to probe amendable therapeutic interventions such as histamine-receptor antagonism.ObjectiveEstablishing an adoptive transfer model for antigen-specific Th cells, we aimed to delineate the role of histamine H1- and H4-receptors in Th2-dependent skin inflammation.Methods In-vitro differentiated and OVA primed Th2 cells were adoptively transferred into congenic recipient mice. In vivo treatment with specific histamine H1- and H4-receptor antagonists was performed to analyze the contribution of these histamine-receptors to Th2-dependent skin pathology in our model. Analysis four days after epicutaneous challenge comprised skin histology, flow cytometric detection of transferred T-helper cells and analysis of antigen-cytokine profiles in skin-draining lymph nodes.ResultsUse of specific H1- and H4-receptor antagonists revealed a crucial role for H1- and H4-receptors for Th2 migration and cytokine secretion in a Th2-driven model of skin inflammation. While H1- and H4-receptor antagonists both reduced Th2 recruitment to the site of challenge, local cytokine responses in skin-draining lymph nodes were only reduced by the combined application of H1- and H4-receptor antagonists and mast cell counts remained altogether unchanged by either H1R-, H4R- or combined antagonism.ConclusionOur model demonstrates a role for H1- and H4-receptors in Th2 cell infiltration and cytokine secretion in allergic skin diseases and suggests further studies to evaluate these findings for therapeutic approaches.

In vitro generation of microbe-specific human Th17 cells.

Th17 cells represent a T helper cell subset with major implications for the pathogenesis of autoimmune diseases and the clearance of extracellular bacteria and fungi. The in vitro generation of human Th17 cells has been subject to many debates concerning the minimal cytokine requirements for IL-17 induction. This is partly due to the low Th17 cell priming efficiencies that have been reported so far for human as compared to murine T cells. In addition, human T helper cell priming is primarily performed using polyclonal stimulation even though it has recently been reported that cytokine requirements for the generation of Th17 cells may differ depending on the microbial antigen specificities of naïve T cells. Here, we present a detailed procedure on how to efficiently generate microbe-specific Th17 cells from naïve T helper cells.

Generation of protection against Francisella novicida in mice depends on the pathogenicity protein PdpA, but not PdpC or PdpD

Previous results suggest that mutations in most genes in the Francisella pathogenicity island (FPI) attenuate the bacterium. Using a mouse model, here we determined the impact of mutations in pdpA, pdpC, and pdpD in Francisella novicida on in vitro replication in macrophages, and in vivo immunogenicity. In contrast to most FPI genes, deletion of pdpC (FnΔpdpC) and pdpD (FnΔpdpD) from F. novicida did not impact growth in mouse bone-marrow derived macrophages. Nonetheless, both FnΔpdpC and FnΔpdpD were highly attenuated when administered intradermally. Infected mice produced relatively normal anti-F. novicida serum antibodies. Further, splenocytes from infected mice controlled intramacrophage Francisella replication, indicating T cell priming, and mice immunized by infection with FnΔpdpC or FnΔpdpD survived secondary lethal parenteral challenge with either F. novicida or Francisella tularensis LVS. In contrast, deletion of pdpA (FnΔpdpA) ablated growth in macrophages in vitro. FnΔpdpA disseminated and replicated poorly in infected mice, accompanied by development of some anti-F. novicida serum antibodies. However, primed Th1 cells were not detected, and vaccinated mice did not survive even low dose challenge with either F. novicida or LVS. Taken together, these results suggest that successful priming of Th1 cells, and protection against lethal challenge, depends on expression of PdpA.

Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE

EAE, an animal model for multiple sclerosis, is a Th17- and Th1-cell-mediated auto-immune disease, but the mechanisms leading to priming of encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. To investigate the role of dendritic cells (DCs) in the initiation of autoimmune Th17- and Th1-cell responses and EAE, we used mice transgenic for a simian diphtheria toxin receptor (DTR) expressed under the control of the murine CD11c promoter (CD11c-DTR mice o nC57BL/6 background).EAE was induced by immunization with myelin oligodendrocyte glycoprotein (MOG) protein in CFA. DCs were depleted on the day before and 8 days after MOG immunization. The mean clinical EAE score was only mildly reduced in DC-depleted mice when DCs were ablated before EAE induction. The frequency of activated Th cells was not altered, and MOG-induced Th17 or Th1-cell responses were not altered, in the spleens of DC-depleted mice. Similar results were obtained if DCs were ablated the first 10 days after MOG immunization with repeated DC depletions. Unexpectedly, transient depletion of DCs did not affect priming or differentiation of MOG-induced Th17 and Th1-cell responses or the incidence of EAE. Thus, the mechanism of priming of Th cells in EAE remains to be elucidated.

The therapeutic effects of daphnetin in collagen-induced arthritis involve its regulation of Th17 cells

ObjectivesDaphne odora var. marginata (D. marginata), an aiophyllus arbuscular plant, is one of the traditional Chinese medicines used to treat rheumatoid arthritis. This study investigated the therapeutic effects and mechanisms of daphnetin, an active monomer ingredient derived from D. marginata, on collagen-induced arthritis (CIA) in rats. MethodsThe effects of daphnetin on joint diseases were assessed by hematoxylin and eosin staining and radiographic and transmission electron microscopy. The protein and mRNA expression levels of T helper (Th)1/Th2/Th17-type cytokines in the spleen were determined by flow cytometry and quantitative real-time PCR. ResultsOur results showed that daphnetin significantly reduced paw swelling and was nontoxic in vivo at the tested doses. Synovial hyperplasia, joint destruction and chondrocyte degeneration in CIA rats were suppressed by daphnetin. Daphnetin treatment also reduced the levels of Th1/Th2/Th17 type cytokines in spleen lymphocytes in CIA rats. Moreover, the expression of Foxp3, which can down-regulate the activity of Th17 cells, was significantly increased in the daphnetin-treated groups. ConclusionsThese results suggest that daphnetin may have therapeutic effects in down-regulating Th17-type responses in CIA rats. The beneficial effects of daphnetin on CIA may be related to its inhibition of Th17 cell priming and activation.

Priming Microenvironments Dictate Cytokine Requirements for T Helper 17 Cell Lineage Commitment

Activation of pattern recognition receptors on dendritic cells (DCs) and macrophages leads to secretion of cytokines that control differentiation of CD4(+) T cells. The current understanding is that interleukin-6 (IL-6) in combination with transforming growth factor-β (TGF-β) leads to generation of T helper 17 (Th17) lineage cells. Here, we have discovered that the cytokine requirements for Th17 cell polarization depend on the site of priming. Although IL-6 played a critical role in Th17 cell lineage priming in the skin and mucosal tissues, it was not required for Th17 cell priming in the spleen. In contrast, IL-1 played an irreplaceable role for priming of Th17 lineage cells in all tissues. Importantly, we have demonstrated that IL-6-independent and -dependent pathways of Th17 cell differentiation are guided by DCs residing in various tissues. These results reveal fundamental differences by which the systemic, mucosal, and cutaneous immune systems guide Th17 cell lineage commitment.

Estrogen Receptor α Signaling in T Lymphocytes Is Required for Estradiol-Mediated Inhibition of Th1 and Th17 Cell Differentiation and Protection against Experimental Autoimmune Encephalomyelitis

Estrogen treatment exerts a protective effect on experimental autoimmune encephalomyelitis (EAE) and is under clinical trial for multiple sclerosis therapy. Estrogens have been suspected to protect from CNS autoimmunity through their capacity to exert anti-inflammatory as well as neuroprotective effects. Despite the obvious impacts of estrogens on the pathophysiology of multiple sclerosis and EAE, the dominant cellular target that orchestrates the anti-inflammatory effect of 17β-estradiol (E2) in EAE is still ill defined. Using conditional estrogen receptor (ER) α-deficient mice and bone marrow chimera experiments, we show that expression of ERα is critical in hematopoietic cells but not in endothelial ones to mediate the E2 inhibitory effect on Th1 and Th17 cell priming, resulting in EAE protection. Furthermore, using newly created cell type-specific ERα-deficient mice, we demonstrate that ERα is required in T lymphocytes, but neither in macrophages nor dendritic cells, for E2-mediated inhibition of Th1/Th17 cell differentiation and protection from EAE. Lastly, in absence of ERα in host nonhematopoietic tissues, we further show that ERα signaling in T cells is necessary and sufficient to mediate the inhibitory effect of E2 on EAE development. These data uncover T lymphocytes as a major and nonredundant cellular target responsible for the anti-inflammatory effects of E2 in Th17 cell-driven CNS autoimmunity.

Lung myeloid-derived suppressor cells and regulation of inflammation

Myeloid-derived suppressor cells (MDSCs) have been investigated largely in the context of tumor progression. In contrast to the negative connotation of MDSCs in cancer immunity, our laboratory has recently reported on the development and role of pulmonary MDSC-like cells (CD11b(+)Gr1(int)F4/80(+)) in the regulation of allergic airway inflammation. These regulatory cells were expanded in a TLR4/MyD88-dependent manner and were both phenotypically and morphologically similar to those described in the tumor microenvironment. Although bacterial lipopolysaccharide (LPS) was initially described as an adjuvant in the development of allergic inflammation, subsequent studies showed that this is true only at relatively low doses of LPS. A high dose of LPS was shown to actually suppress eosinophilic airway inflammation. In our efforts to understand the mechanism underlying LPS-mediated suppression of allergic airway disease, we recently showed that LPS induces MDSC-like cells in the lung tissue in a dose-dependent manner, with increased accumulation of the cells at high doses of LPS. In contrast to lung dendritic cells (DCs), the MDSC-like cells did not traffic to the lung-draining lymph nodes, allowing them to act in a dominant fashion over DCs in the regulation of Th2 responses. The MDSC-like cells were found to blunt the ability of the lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in Th2 effector function. Thus, a complete understanding of the generation and regulation of the lung MDSCs would provide novel options for therapeutic interventions.

PAR2 Promotes Vaccine-Induced Protection Against Helicobacter Infection in Mice

Protective immunization limits Helicobacter infection of mice by undetermined mechanisms. Protease-activated receptor 2 (PAR2) signaling is believed to regulate immune and inflammatory responses. We investigated the role of PAR2 in vaccine-induced immunity against Helicobacter infection. Immune responses against Helicobacter infection were compared between vaccinated PAR2-/- and wild-type (WT) mice. Bacterial persistence, gastric pathology, and inflammatory and cellular responses were assessed using the rapid urease test (RUT), histologic analyses, quantitative polymerase chain reaction, and flow cytometry, respectively. Following vaccination, PAR2-/- mice did not have reductions in Helicobacter felis infection (RUT values were 0.01±0.01 for WT mice and 0.11±0.13 for PAR2-/- mice; P<.05). The vaccinated PAR2-/- mice had reduced inflammation-induced stomach tissue damage (tissue damage scores were 8.83±1.47 for WT mice and 4.86±1.35 for PAR2-/- mice; P<.002) and reduced T-helper (Th)17 responses, based on reduced urease-induced interleukin (IL)-17 secretion by stomach mononuclear cells (5182 ± 1265 pg/mL for WT mice and 350±436 pg/mL for PAR2-/- mice; P<.03) and reduced recruitment of CD4+ IL-17+ T cells into the gastric mucosa of PAR2-/- mice following bacterial challenge (3.7%±1.5% for WT mice and 2.6%±1.1% for PAR2-/- mice; P<.05). In vitro, H felis-stimulated dendritic cells (DCs) from WT mice induced greater secretion of IL-17 by ovalbumin-stimulated OT-II transgenic CD4+ T cells compared with DCs from PAR2-/- mice (4298±347 and 3230±779; P<.04), indicating that PAR2-/- DCs are impaired in priming of Th17 cells. Adoptive transfer of PAR2+/+ DCs into vaccinated PAR2-/- mice increased vaccine-induced protection (RUT values were 0.11±0.10 and 0.26±0.15 for injected and noninjected mice, respectively; P<.03). PAR2 activates DCs to mediate vaccine-induced protection against Helicobacter infection in mice.

β2-Adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response

This study tested the hypothesis that activation of β2-adrenoceptors on DCs influences NOD2 signaling along with its cross-talk with Toll-like receptor-2 resulting in altered Th cell priming ability. Th17 cells are a newly discovered lineage of CD4 + T cells involved in defense against extracellular bacteria and also implicated in autoimmune disorders. Initiation and polarization of the adaptive immune response is controlled by innate immune recognition mediated by DCs. Previous studies demonstrated that adrenergic receptors modulate cytokine production by DCs and affect their Th cell priming ability. We show that the β2-adrenoceptor agonist salbutamol enhanced IL-6 production in murine bone marrow-derived DCs stimulated with the nucleotide-binding oligomerization domain 2 ligand muramyl dipeptide. However, when the Toll-like receptor-2 ligand Pam3CysSK4 was added, salbutamol inhibited IL-12 but did not alter IL-6 and IL-23 expression. Gene expression analysis showed that salbutamol inhibited the p40 subunit as well as IL-12p35, while IL-23p19 and IL-6 were stimulated. Therefore, β2-adrenoceptors modulated cytokine production resulting in a Th17 cell priming cytokine pattern. Indeed, when antigen-pulsed DCs stimulated by muramyl dipeptide or Pam3CysSK4 + muramyl dipeptide in the presence of salbutamol were used for in vivo immunization, the resulting Th17/Th1 cell ratio was increased as evaluated by IL-17 and IFN-γ production. In addition, intradermal injection of norepinephrine along with Pam3CysSK4 + muramyl dipeptide increased the Th17 response to an immunogenic protein and this effect was reversed by a β2-adrenoceptor antagonist. Thus, β2-adrenoceptors may be involved in the regulation of defense against extracellular bacteria and the pathogenesis of inflammatory diseases.

The NKT cell ligand αgalactosylceramide suppresses allergic airway inflammation by induction of a Th1 response

One experimental approach for the treatment of allergic reactions is the stimulation of immunoregulatory NKT cells with the synthetic glycolipid αgalactosylceramide. For a first evaluation of the immunomodulatory potential of αGalCerMPEG a human in vitro allergy model was exploited. Acting as an adjuvant, the glycolipid induced an enhanced Th1-biased allergen-specific immune response of autologous lymphocytes. In a mouse model of allergic airway inflammation, αGalCerMPEG-activated NKT cells promoted a cytokine environment in the spleen, leading to priming of Th1 cells. The shift towards a Th1-dominated allergen-specific immune response thus might mediate the abrogation of allergic airway inflammation and thereby might provide a valid option for therapeutic intervention.

LPS-induced CD11b+Gr1intF4/80+ myeloid cells suppress allergic airway inflammation (55.3)

Abstract The bacterial product lipopolysaccharide (LPS) has been associated with protection from allergic diseases such as asthma in humans. However, differential effects of LPS based on the dose have been noted in the mouse models of allergic asthma. Our recent work has described the ability of LPS to increase the frequency of CD11b+Gr1intF4/80+ cells in the lung tissue of mice in a dose-dependent fashion that is dependent on TLR4 and MyD88. Although the Gr1int cells are readily detectable in the lung tissue of LPS-treated mice, they are not detected in the lung-draining lymph nodes or in the airway lumen which causes selective enrichment of these cells over dendritic cells (DCs) in the tissue. The Gr1int cells were found to blunt the ability of lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in Th2 effector function. Suppression of Th2 effector function was reversed by anti-interleukin-10 or inhibition of arginase 1. Adoptive transfer of LPS-induced Gr1int cells suppressed allergen-induced airway inflammation suggesting that these myeloid cells may have regulatory functions in allergic asthma. Thus, a complete understanding of the generation and regulation of the Gr1int cells would provide new avenues to either promote or delete these cells for disease-specific immunoregulation.

Dimeric galectin-1 alters the plasticity and commitment of Th1 and Th17 cells by promoting IL-10 expression.(152.20)

Abstract Plasticity and commitment of T helper (Th) cell lineages are concepts still under debate. Galectin-1 (Gal-1), a β-galactoside-binding protein, was originally thought to mediate immunoregulation exclusively through its pro-apoptotic effects on activated leukocytes; however, new data suggests that Gal-1 also promotes Th2 skewing, and synthesis of tolerogenic dendritic cells driving differentiation of Type 1 regulatory (Tr1) cells. In this report, using our dimeric Gal-1 hFc, we demonstrate that Th1 and Th17 cells express similar Gal-1-binding glycoprotein repertoires and specifically, CD45, as a predominant binding partner. Furthermore, we show that, at high micromolar concentrations, Gal-1hFc drives caspase-independent apoptosis on Th1 and Th17 cells characterized by nuclear translocation of mitochondrial endonuclease G, but not cytochrome c release. Additionally, at a 10-fold lower concentration, Gal-1hFc incubations during Th1 and Th17 cell priming or after full differentiation caused both pro-inflammatory subsets to synthesize IL-10. In vivo confirmation using murine B16 melanoma cells overexpressing (B16 Gal-1hi) or deficient in Gal-1 (B16 Gal-1KD) showed that mice inoculated with B16 Gal-1hi cells contained higher levels of IL-10+ Th1 and Th17 cells than mice inoculated with B16Gal-1KD cells. This novel property reinforces Gal-1’s role in immune evasion of cancer and highlights its importance as a molecular ‘thermostat’ to help control T cell-mediated inflammation.

Foxp3+ Regulatory T Cells Promote T Helper 17 Cell Development In Vivo through Regulation of Interleukin-2

T helper 17 (Th17) cell development is driven by cytokines including transforming growth factor-β (TGF-β), interleukin-6 (IL-6), IL-1, and IL-23. Regulatory T (Treg) cells can provide the TGF-β invitro, but their role invivo remains unclear, particularly because Treg cells inhibit inflammation in many models of Th17 cell-associated autoimmunity. We used mice expressing Diphtheria toxin receptor under control of the Foxp3 promoter to deplete Foxp3(+) Treg cells in adult mice during invivo Th17 cell priming. Treg cell depletion resulted in a reduced frequency of antigen-specific IL-17 producers in draining lymph nodes and blood, correlating with reduced inflammatory skin responses. In contrast, Treg cells did not promote IL-17 secretion after initial activation stages. Treg cell production of TGF-β was not required for Th17 cell promotion, and neither was suppression of Th1 cell-associated cytokines. Rather, regulation of IL-2 availability and resultant signaling through CD25 by Treg cells was found to play an important role.

H-2 alleles contribute to antigen 85-specific interferon-gamma responses during Mycobacterium tuberculosis infection

The in vitro immune responses to mycobacterial antigens have been linked to the H-2 loci in mice. We evaluated in vitro and in vivo immune responses during early Mycobacterium tuberculosis (M.tb) pulmonary infection of C57BL/6 (H-2b), C57BL/6 (H-2k), CBA/J (H-2k), and C3H/HeJ (H-2k) mice to determine H-2k-dependent and -independent effects. H-2k-dependent effects included delayed and diminished Ag85-specific Th1 cell priming, a reduced frequency of Ag85-specific IFN-γ producing cells, reduced IFN-γ protein in vivo, and increased M.tb lung burden as demonstrated by C57BL/6 H-2k mice vs. C57BL/6 mice. H-2k-independent factors controlled the amount of Ag85-specific IFN-γ produced by each cell, T cell numbers, granuloma size, and lymphocytic infiltrates in the lungs. Overall, these results suggest that an H-2k-dependent suboptimal generation of Ag85-specific cells impairs control of early M.tb growth in the lungs. H-2k-independent factors influence the potency of IFN-γ producing cells and immune cell trafficking during pulmonary M.tb infection.

TLR4/MyD88-induced CD11b+Gr-1intF4/80+ non-migratory myeloid cells suppress Th2 effector function in the lung

In humans, environmental exposure to a high dose of lipopolysaccharide (LPS) protects from allergic asthma, the immunological underpinnings of which are not well understood. In mice, exposure to a high LPS dose blunted house dust mite-induced airway eosinophilia and T-helper 2 (Th2) cytokine production. Although adoptively transferred Th2 cells induced allergic airway inflammation in control mice, they were unable to do so in LPS-exposed mice. LPS promoted the development of a CD11b+Gr1intF4/80+ lung-resident cell resembling myeloid-derived suppressor cells in a Toll-like receptor 4 and myeloid differentiation factor 88 (MyD88)-dependent manner that suppressed lung dendritic cell (DC)-mediated reactivation of primed Th2 cells. LPS effects switched from suppressive to stimulatory in MyD88−/− mice. Suppression of Th2 effector function was reversed by anti-interleukin-10 (IL-10) or inhibition of arginase 1. Lineageneg bone marrow progenitor cells could be induced by LPS to develop into CD11b+Gr1intF4/80+cells both in vivo and in vitro that when adoptively transferred suppressed allergen-induced airway inflammation in recipient mice. These data suggest that CD11b+Gr1intF4/80+ cells contribute to the protective effects of LPS in allergic asthma by tempering Th2 effector function in the tissue.