Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors RORγt and Ahr that leads to IL-17 production by activated B cells.

Here we identified B cells as a major source of rapid, innate-like production of interleukin 17 (IL-17) in vivo in response to infection with Trypanosoma cruzi. IL-17(+) B cells had a plasmablast phenotype, outnumbered cells of the TH17 subset of helper T cells and were required for an optimal response to this pathogen. With both mouse and human primary B cells, we found that exposure to parasite-derived trans-sialidase in vitro was sufficient to trigger modification of the cell-surface mucin CD45, which led to signaling dependent on the kinase Btk and production of IL-17A or IL-17F via a transcriptional program independent of the transcription factors RORγt and Ahr. Our combined data suggest that the generation of IL-17(+) B cells may be a previously unappreciated feature of innate immune responses required for pathogen control or IL-17-mediated autoimmunity.

Helminth-induced regulation of T-cell transfer colitis requires intact and regulated T cell Stat6 signaling in mice.

Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.

Effector functions of Th17 cells are regulated by IL-35 and TGF-ß in visceral leishmaniasis.

Visceral leishmaniasis (VL) is a debilitating human pathogenesis in which the body's immune functions are severely compromised. Various subsets of T cells, including Th17 cells are important regulators of immune responses observed in various pathologies. The role of Th17 cells and its correlation with immuno-regulatory cytokines are however not well understood in human VL. Herein we studied how IL-17 is associated with the progression of Leishmania donovani infection using murine model of VL. We found induction of a strong IL-17 response at the early phase of infection which progressively reduced to basal level during chronic VL. The mechanistic study of this behavior was found to be linked with the role of regulatory T cells (CD4+ CD25+ T cells) that suppresses the proliferation of the Th17 cell population. Moreover, TGF-ß and IL-35 derived from CD4+ CD25+ T cells are the key mediators for the downregulation of IL-17 during chronic VL. Thus, this study points to an antagonistic effect of Tregs and Th17 cells that can be used for designing better therapeutic and preventive strategies against leishmaniasis.

TGFß-activation by dendritic cells drives Th17 induction and intestinal contractility and augments the expulsion of the parasite Trichinella spiralis in mice.

Helminths are highly prevalent metazoan parasites that infect over a billion of the world's population. Hosts have evolved numerous mechanisms to drive the expulsion of these parasites via Th2-driven immunity, but these responses must be tightly controlled to prevent equally devastating immunopathology. However, mechanisms that regulate this balance are still unclear. Here we show that the vigorous Th2 immune response driven by the small intestinal helminth Trichinella spiralis, is associated with increased TGFß signalling responses in CD4+ T-cells. Mechanistically, enhanced TGFß signalling in CD4+ T-cells is dependent on dendritic cell-mediated TGFß activation which requires expression of the integrin αvß8. Importantly, mice lacking integrin αvß8 on DCs had a delayed ability to expel a T. spiralis infection, indicating an important functional role for integrin αvß8-mediated TGFß activation in promoting parasite expulsion. In addition to maintaining regulatory T-cell responses, the CD4+ T-cell signalling of this pleiotropic cytokine induces a Th17 response which is crucial in promoting the intestinal muscle hypercontractility that drives worm expulsion. Collectively, these results provide novel insights into intestinal helminth expulsion beyond that of classical Th2 driven immunity, and highlight the importance of IL-17 in intestinal contraction which may aid therapeutics to numerous diseases of the intestine.

The Potential Role of Schistosome-Associated Factors as Therapeutic Modulators of the Immune System.

The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders, including allergies, autoimmune diseases, and alloimmune responses. Recently, there has been increasing research interest in the role of schistosomes in immunoregulation during human infection, and the mechanisms underlying these roles continue to be investigated. Further studies may identify potential opportunities to develop new treatments for immune disease. In this review, we provide an update on the advances in our understanding of schistosome-associated modulation of the cells of the innate and adaptive immune systems as well as the potential role of schistosome-associated factors as therapeutic modulators of immune disorders, including allergies, autoimmune diseases, and transplant immunopathology. We also discuss potential opportunities for targeting schistosome-induced immunoregulation for future translation to the clinical setting.

Plasmodium yoelii 17XL infection modified maturation and function of dendritic cells by skewing Tregs and amplificating Th17.

BACKGROUND: Emerging data has suggested that Tregs, Th17, Th1 and Th2 are correlated with early immune mechanisms by controlling Plasmodium infection. Plasmodium infection appeared to impair the antigen presentation and maturation of DCs, leading to attenuation of specific cellular immune response ultimately. Hence, in this study, we aim to evaluate the relevance between DCs and Tregs/Th17 populations in the process and outcomes of infection with Plasmodium yoelii 17XL (P.y17XL). METHODS: DCs detection/analysis dynamically was performed by Tregs depletion or Th17 neutralization in P.y17XL infected BALB/c mice via flow cytometry. Then the levels of cytokines production were detected using enzyme-linked mmunosorbent assay (ELISA). RESULTS: Our results indicated that Tregs depletion or Th17 neutralization in BALB/c mice infected with P.y17XL significantly up-regulated the percentages of mDC and pDC, increased the expressions of major histocompatibility complex (MHC) class II, CD80, CD86 on DCs and the levels of IL-10/IL-12 secreted by DCs, indicating that abnormal amplification of Tregs or Th17 may damage the maturation and function of DCs during the early stage of malaria infection. Interestingly, we also found that the abnormal amplification of Th17, as well as Tregs, could inhibit the maturation of DCs. CONCLUSIONS: Tregs skewing or Th17 amplification during the early stage of malaria infection may inhibit the maturation and function of DCs by modifying the subsets of DCs, expressions of surface molecules on DCs and secretion mode of cytokines.

Live Attenuated Leishmania donovani Centrin Gene-Deleted Parasites Induce IL-23-Dependent IL-17-Protective Immune Response against Visceral Leishmaniasis in a Murine Model.

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene-deleted Leishmania donovani (LdCen-/- ) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen-/- -induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen-/- parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen-/- Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen-/- -immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-γ-producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN-γ abrogated LdCen-/- -induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R-/- mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17-mediated protection by LdCen-/- parasites. This study unveiled the role of IL-23-dependent IL-17 induction in LdCen-/- parasite-induced immunity and subsequent protection against visceral leishmaniasis.

IL-17 and IL-22 elicited by a DNA vaccine encoding ROP13 associated with protection against Toxoplasma gondii in BALB/c mice.

Toxoplasma gondii, an intracellular parasitic protozoan, is capable of infecting man and all warm-blooded animals. Cell-mediated immunity is vital in mounting protective responses against T. gondii infection. Recent studies have shown that T-helper (Th) 17 responses may play a key role in parasite control. In this current study, we constructed a DNA vaccine encoding T. gondii ROP13 in a pcDNA vector. Groups of BALB/c mice were immunized intramuscularly with pcROP13 or controls and challenged with the RH strain of T. gondii. The results showed that immunization with pcROP13 could elicit an antibody response against T. gondii. The expression of the canonical Th17 cytokines, interleukin (IL)-17 and IL-22, were significantly increased after immunization with pcROP13 compared with control groups ( p < 0.05). Furthermore, vaccination resulted in a significant decrease in parasite load ( p < 0.05). The induction of Th17 related cytokines, using a ROP13 DNA vaccine, against T. gondii should be considered as a potential vaccine approach for the control of toxoplasmosis.

Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions.

The tumour-like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococcosis, AE) is directly linked to the nature/orientation of the periparasitic host immune-mediated processes. Parasite-mediated immune suppression is a hallmark triggering infection outcome in both chronic human and murine AE. So far, little is known about secondary systemic immune effects of this pathogen on other concomitant diseases, e.g. endogenous gut inflammation. We examined the influence of E. multilocularis infection on murine dextran sodium sulphate (DSS) -induced colitis. At 3 months after E. multilocularis infection (chronic stage), the mice were challenged with 3% DSS in the drinking water for 5 days plus subsequently with tap water (alone) for another 4 days. After necropsy, fixed tissues/organs were sectioned and stained with haematoxylin & eosin for assessing inflammatory reactions. Cytokine levels were measured by flow cytometry and quantitative RT-PCR. Colitis severity was assessed (by board-certified veterinary pathologists) regarding (i) colon length, (ii) weight loss and (iii) a semi-quantitative score of morphological changes. The histopathological analysis of the colon showed a significant reduction of DSS-induced gut inflammation by concomitant E. multilocularis infection, which correlated with down-regulation of T helper type 1 (Th1)/Th17 T-cell responses in the colon tissue. Echinococcus multilocularis infection markedly reduced the severity of DSS-induced gut inflammation upon down-regulation of Th1/Th17 cytokine expression and attenuation of CD11b+ cell activation. In conclusion, E. multilocularis infection remarkably reduces DSS-induced colitis in mice by attenuating Th1/Th17-mediated immune reactions.

Modulation of CD4+ and CD8+ T Cell Function and Cytokine Responses in Strongyloides stercoralis Infection by Interleukin-27 (IL-27) and IL-37.

Strongyloides stercoralis infection is associated with diminished antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4+ and CD8+ T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis-infected individuals and 10 uninfected individuals stimulated with parasite antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with parasite antigen stimulation. There was no induction of any T cell response in uninfected individuals following parasite antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection.

Parasite Antigen-Specific Regulation of Th1, Th2, and Th17 Responses in Strongyloides stercoralis Infection.

Chronic helminth infections are known to be associated with modulation of Ag-specific CD4(+) T responses. However, the role of CD4(+) T cell responses in human infection with Strongyloides stercoralis is not well defined. To examine the role of CD4(+) T cells expressing Th1, Th2, and Th17 cytokines in strongyloidiasis, we compared the frequency (Fo) of these subsets in infected (INF) individuals with Fo in S. stercoralis-uninfected (UN) individuals. INF individuals exhibited a significant decrease in the spontaneous and Ag-specific Fo of both monofunctional and dual-functional Th1 cells compared with UN. Similarly, INF individuals also exhibited significantly decreased Fo of monofunctional and dual-functional Th17 cells upon Ag stimulation compared with UN. In contrast, both the spontaneous and the Ag-induced Fo of monofunctional and dual-functional Th2 cells was significantly increased in INF compared with UN individuals. This differential T cell response was predominantly Ag specific because it was abrogated upon control Ag or mitogen stimulation. The regulation of Th1, Th2, and Th17 cells was predominantly dependent on IL-10, whereas the regulation of Th2, but not Th1 or Th17, cells was also dependent on TGF-ß. In addition, treatment of S. stercoralis infection significantly increased the Ag-specific Fo of Th1 and Th17 cells and decreased the Fo of Th2 cells in INF individuals. Thus, S. stercoralis infection is characterized by a parasite Ag-dependent regulation of monofunctional and dual-functional Th1, Th2, and Th17 cells, a regulation also reversible by antihelminthic treatment.

Regulatory T-cell neutralization in mice during filariasis helps in parasite clearance by enhancing T helper type 17-mediated pro-inflammatory response.

Lymphatic filariasis leads to profound impairment of parasite-specific T helper type 1 (Th1) and Th2 immune responses and significantly increases the expression of regulatory networks and regulatory effectors like transforming growth factor-ß, CD25, cytotoxic T-lymphocyte antigen 4, glucocorticoid-induced tumour necrosis factor receptor (GITR) and regulatory T (Treg) cells, which together play an important role in immunosuppression. While Treg cells suppress the activity of effector cells, monocyte dysfunction, characterized by an alternatively activated immunoregulatory phenotype, is one hypothesis that explains the lack of an antigen-specific T-cell response in infected individuals. In the present study, we administered neutralizing antibodies against the Treg cell-associated markers CD25 and GITR and observed its effects on filaria-induced immunosuppression. Our results show that administration of anti-CD25 and anti-GITR in infected animals not only arrested the accumulation of Treg cells and reduced arginase activity, but also led to an increase in the percentages of Th17 cells in the secondary lymphoid organs of mice. Elevated levels of interferon-γ and decreased levels of interleukin-10 were also noted in the culture supernatants of mouse splenocytes that were treated with neutralizing antibodies. Furthermore, treatment with neutralizing antibodies enhanced the expression of inducible nitric oxide synthase on host macrophages and CD40 on host dendritic cells with concomitant decreased expression of alternative activation markers Arg1, Ym1 and Fizz1, which together lead to reduced parasite burden in treated animals. In summary, administration of neutralizing antibodies helps in breaking the regulatory network in mice and limits parasite-induced immunosuppression at the earliest host-parasite interface.

Toll-like receptor 9 signaling in dendritic cells regulates neutrophil recruitment to inflammatory foci following Leishmania infantum infection.

Leishmania infantum is a protozoan parasite that causes visceral leishmaniasis (VL). This infection triggers dendritic cell (DC) activation through the recognition of microbial products by Toll-like receptors (TLRs). Among the TLRs, TLR9 is required for DC activation by different Leishmania species. We demonstrated that TLR9 is upregulated in vitro and in vivo during infection. We show that C57BL/6 mice deficient in TLR9 expression (TLR9(-/-) mice) are more susceptible to infection and display higher parasite numbers in the spleen and liver. The increased susceptibility of TLR9(-/-) mice was due to the impaired recruitment of neutrophils to the infection foci associated with reduced levels of neutrophil chemoattractants released by DCs in the target organs. Moreover, both Th1 and Th17 cells were also committed in TLR9(-/-) mice. TLR9-dependent neutrophil recruitment is mediated via the MyD88 signaling pathway but is TIR domain-containing adapter-inducing interferon beta (TRIF) independent. Furthermore, L. infantum failed to activate both plasmacytoid and myeloid DCs from TLR9(-/-) mice, which presented reduced surface costimulatory molecule expression and chemokine release. Interestingly, neutrophil chemotaxis was affected both in vitro and in vivo when DCs were derived from TLR9(-/-) mice. Our results suggest that TLR9 plays a critical role in neutrophil recruitment during the protective response against L. infantum infection that could be associated with DC activation.

Modulation of mycobacterial-specific Th1 and Th17 cells in latent tuberculosis by coincident hookworm infection.

Hookworm infections and tuberculosis (TB) are coendemic in many parts of the world. It has been suggested that infection with helminth parasites could suppress the predominant Th1 (IFN-γ-mediated) response needed to control Mycobacterium tuberculosis infection and enhance susceptibility to infection and/or disease. To determine the role of coincident hookworm infection on responses at steady-state and on M. tuberculosis-specific immune responses in latent TB (LTB), we examined the cellular responses in individuals with LTB with or without concomitant hookworm infection. By analyzing the expression of Th1, Th2, and Th17 subsets of CD4(+) T cells, we were able to demonstrate that the presence of coincident hookworm infection significantly diminished both spontaneously expressed and M. tuberculosis-specific mono- and dual-functional Th1 and Th17 cells. Hookworm infection, in contrast, was associated with expanded frequencies of mono- and dual-functional Th2 cells at both steady-state and upon Ag stimulation. This differential induction of CD4(+) T cell subsets was abrogated upon mitogen stimulation. Additionally, coincident hookworm infection was associated with increased adaptive T regulatory cells but not natural regulatory T cells in LTB. Finally, the CD4(+) T cell cytokine expression pattern was also associated with alterations in the systemic levels of Th1 and Th2 cytokines. Thus, coincident hookworm infection exerts a profound inhibitory effect on protective Th1 and Th17 responses in LTB and may predispose toward the development of active tuberculosis in humans.

Regulation of proinflammatory Th17 responses during Trypanosoma cruzi infection by IL-12 family cytokines.

Previously, we reported that the transcription factor T-bet (Tbx21) regulates Th17 responses to Trypanosoma cruzi infection in an IFN-γ-independent manner. In an effort to further understand this regulation, we examined the development and plasticity of Th17 cells during T. cruzi infection. Th17 cells recovered from infected Tbx21(-/-) mice were amenable to the inhibitory effects of T-bet, as ectopic expression of T-bet reduced IL-17 expression. We subsequently addressed the role of IL-12 family cytokines IL-12 and IL-27 and report that IL-12p35(-/-) mice infected with T. cruzi exhibited a significant increase in Th17 cells and Th17-associated inflammation. Ex vivo culture of these cells with IL-12 led to a dramatic reduction in IL-17 production and concomitant increase in IFN-γ. Importantly, the ability of IL-12 to suppress IL-17 was independent of IFN-γ. Surprisingly, and contrary to results reported for other pathogens, IL-27 had no inhibitory effect on Th17 development, as Ebi-3(-/-) mice failed to show any increase in their T. cruzi-specific Th17 response. Furthermore, IL-27 could not compensate or synergize with IL-12 to suppress IL-17 production ex vivo. Thus, we have established that IL-12, not IL-27, is critical for regulating Th17 responses to T. cruzi.

IL-22 mediates host defense against an intestinal intracellular parasite in the absence of IFN-γ at the cost of Th17-driven immunopathology.

The roles of Th1 and Th17 responses as mediators of host protection and pathology in the intestine are the subjects of intense research. In this study, we investigated a model of intestinal inflammation driven by the intracellular apicomplexan parasite Eimeria falciformis. Although IFN-γ was the predominant cytokine during E. falciformis infection in wild-type mice, it was found to be dispensable for host defense and the development of intestinal inflammation. E. falciformis-infected IFN-γR(-/-) and IFN-γ(-/-) mice developed dramatically exacerbated body weight loss and intestinal pathology, but they surprisingly harbored fewer parasites. This was associated with a striking increase in parasite-specific IL-17A and IL-22 production in the mesenteric lymph nodes and intestine. CD4(+) T cells were found to be the source of IL-17A and IL-22, which drove the recruitment of neutrophils and increased tissue expression of anti-microbial peptides (RegIIIß, RegIIIγ) and matrix metalloproteinase 9. Concurrent neutralization of IL-17A and IL-22 in E. falciformis-infected IFN-γR(-/-) mice resulted in a reduction in infection-induced body weight loss and inflammation and significantly increased parasite shedding. In contrast, neutralization of IL-22 alone was sufficient to increase parasite burden, but it had no effect on body weight loss. Treatment of an E. falciformis-infected intestinal epithelial cell line with IFN-γ, IL-17A, or IL-22 significantly reduced parasite development in vitro. Taken together, to our knowledge these data demonstrate for the first time an antiparasite effect of IL-22 during an intestinal infection, and they suggest that IL-17A and IL-22 have redundant roles in driving intestinal pathology in the absence of IFN-γ signaling.

The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1ß.

CBA/J mice infected with the helminth Schistosoma mansoni develop severe CD4 T cell-mediated hepatic granulomatous inflammation against parasite eggs associated with a robust Th17 cell response. We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by transgenic T cells, whereas exogenous IL-23 or IL-1ß reconstituted their ability to produce IL-17 when stimulated by syngeneic IL-12p40-deficient dendritic cells. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1ß. Significantly, schistosome-infected IL-12p40-deficient or IL-1R antagonist-treated CBA/J mice developed markedly reduced hepatic immunopathology with a dampened egg Ag-specific IL-17 response. These results demonstrate that the IL-23-IL-1-IL-17 axis has a central role in the development of severe schistosome egg-induced immunopathology.

Exacerbated egg-induced immunopathology in murine Schistosoma mansoni infection is primarily mediated by IL-17 and restrained by IFN-γ.

In schistosomiasis, the severity of CD4(+) T-cell-mediated hepatic granulomatous inflammation against parasite eggs varies considerably in humans and among mouse strains. In C57BL/6 mice, pronounced exacerbation of immunopathology induced by immunization with schistosome egg Ag in CFA (SEA/CFA) substantially recapitulates the natural high pathology seen in CBA mice; both are associated with a significant elevation of Th17- and Th1-cell-derived proinflammatory cytokines. We now investigated the relative contribution of the effector cytokines IL-17 and IFN-γ in pathology development of 7 wk-infected, SEA/CFA-immunized, IL-17(-/-) , IFN-γ(-/-) , and IL-17/IFN-γ(-/-) mice. In IL-17(-/-) mice there was significant reduction of immunopathology despite increased levels of IFN-γ, whereas in IFN-γ(-/-) mice, markedly exacerbated immunopathology correlated with an increase in IL-17. In IL-17/IFN-γ(-/-) mice, complete resistance to SEA/CFA-induced disease exacerbation was associated with a reduction in IL-23p19, IL-1ß, CXCL1 and iNOS, and with an increase in IL-5, IL-10 and Relmα. IL-17 and IFN-γ were derived from distinct CD4(+) T cells in which production of each cytokine was suppressed by the other. Our results indicate that severe immunopathology in murine schistosomiasis is mainly driven by IL-17 and regulated by IFN-γ; however, in the absence of IL-17, IFN-γ is capable of exerting a limited, yet significant, pathogenic function.

MiR-374b-5p Regulates T Cell Differentiation and Is Associated with rEg.P29 Immunity.

Cystic echinococcosis (CE) is a zoonotic disease caused by Echinococcus granulosus (Eg) infection. Our previous study confirmed that recombinant Eg.P29 (rEg.P29) could protect against echinococcus granulosus secondary infection in sheep and mice. The aim of the study was to investigate the association between immunoprotection of rEg.P29 vaccine and mmu-miR-374b-5p (miR-374b-5p) and study the immunity influence of miR-374b-5p on CD4+ T cells in mice spleen. MiR-374b-5p level was significantly increased after the second-week and the fourth week of vaccination with rEg.P29. Overexpression of miR-374b-5p increased IFN-γ, IL-2, IL-17A mRNA levels and decreased IL-10 mRNA levels in CD4+ T cells. Moreover, the inhibition of miR-374b-5p decreased IFN-γ and IL-17A and increased IL-10 mRNA levels in CD4+ T cells; this was further confirmed by the flow cytometry. The vaccination of rEg.P29 enhanced miR-374b-5p expression that was associated with a higher Th1 and Th17 immune response, a lower IL-10 mRNA production with miR-374b-5p overexpression, a lower Th1 immune response, and a higher IL-10 mRNA levels with miR-374b-5p inhibitions. To sum up, these data suggest that miR-374b-5p may participate in rEg.P29 immunity by regulating Th1 and Th17 differentiation.

Wuchereria bancrofti filaria activates human dendritic cells and polarizes T helper 1 and regulatory T cells via toll-like receptor 4.

Interaction between innate immune cells and parasite plays a key role in the immunopathogenesis of lymphatic filariasis. Despite being professional antigen presenting cells critical for the pathogen recognition, processing and presenting the antigens for mounting T cell responses, the dendritic cell response and its role in initiating CD4+ T cell response to filaria, in particular Wuchereria bancrofti, the most prevalent microfilaria is still not clear. Herein, we demonstrate that a 70 kDa phosphorylcholine-binding W. bancrofti sheath antigen induces human dendritic cell maturation and secretion of several pro-inflammatory cytokines. Further, microfilarial sheath antigen-stimulated dendritic cells drive predominantly Th1 and regulatory T cell responses while Th17 and Th2 responses are marginal. Mechanistically, sheath antigen-induced dendritic cell maturation, and Th1 and regulatory T cell responses are mediated via toll-like receptor 4 signaling. Our data suggest that W. bancrofti sheath antigen exploits dendritic cells to mediate distinct CD4+ T cell responses and immunopathogenesis of lymphatic filariasis.