scholarly journals Protective CD4+ Th1 cell-mediated immunity is reliant upon execution of effector function prior to the establishment of the pathogen niche

2021 ◽  
Vol 17 (9) ◽  
pp. e1009944
Author(s):  
Leah S. Hohman ◽  
Zhirong Mou ◽  
Matheus B. Carneiro ◽  
Gabriel Ferland ◽  
Rachel M. Kratofil ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Host Cells ◽  
Secondary Site ◽  
Cell Mediated Immunity ◽  
Th1 Cells ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Inflammatory Monocytes ◽  
Adaptive Immune Cells ◽  
Concomitant Immunity

Intracellular infection with the parasite Leishmania major features a state of concomitant immunity in which CD4+ T helper 1 (Th1) cell-mediated immunity against reinfection coincides with a chronic but sub-clinical primary infection. In this setting, the rapidity of the Th1 response at a secondary site of challenge in the skin represents the best correlate of parasite elimination and has been associated with a reversal in Leishmania-mediated modulation of monocytic host cells. Remarkably, the degree to which Th1 cells are absolutely reliant upon the time at which they interact with infected monocytes to mediate their protective effect has not been defined. In the present work, we report that CXCR3-dependent recruitment of Ly6C+ Th1 effector (Th1EFF) cells is indispensable for concomitant immunity and acute (<4 days post-infection) Th1EFF cell-phagocyte interactions are critical to prevent the establishment of a permissive pathogen niche, as evidenced by altered recruitment, gene expression and functional capacity of innate and adaptive immune cells at the site of secondary challenge. Surprisingly, provision of Th1EFF cells after establishment of the pathogen niche, even when Th1 cells were provided in large quantities, abrogated protection, Th1EFF cell accumulation and IFN-γ production, and iNOS production by inflammatory monocytes. These findings indicate that protective Th1 immunity is critically dependent on activation of permissive phagocytic host cells by preactivated Th1EFF cells at the time of infection.

scholarly journals Potentiality of Interleukin-18 as a Useful Reagent for Treatment and Prevention of Leishmania major Infection

2000 ◽  
Vol 68 (5) ◽  
pp. 2449-2456 ◽  
Author(s):  
Kazunobu Ohkusu ◽  
Tomohiro Yoshimoto ◽  
Kiyoshi Takeda ◽  
Takeharu Ogura ◽  
Shin-ichiro Kashiwamura ◽  
...  
Keyword(s):  
Cell Activation ◽  
Leishmania Major ◽  
Killer Cell ◽  
Protective Role ◽  
Daily Injection ◽  
Th1 Cells ◽  
Interleukin 18 ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Ifn Γ

ABSTRACT Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in natural killer cell activation and the T helper 1 (Th1) cell response, particularly in collaboration with IL-12. Since Th1 cells play a pivotal role in the host defense against infection with intracellular microbes, such as Leishmania major, we investigated whether IL-18 is critically involved in protection againstL. major infection by activation of Th1 cells. We administered IL-12 and/or IL-18 daily to L. major-susceptible BALB/c mice. Neither IL-12 (10 ng/mouse) nor IL-18 (1,000 ng/mouse) induced wound healing, while daily injection of IL-12 and IL-18 during the first week after infection strongly protected the mice from footpad swelling by induction and activation of Th1 cells. Furthermore, these mice acquired protective immunity. We also investigated a protective role of endogenous IL-18 by using anti-IL-18 antibody-treated C3H/HeN mice (an L. major-resistant strain) or IL-18 deficient (IL-18−/−) mice with a resistant background (C57BL/6). We found that in the absence of endogenous IL-18, these mice showed prolonged footpad swelling as well as diminished nitric oxide production. However, daily injection of IL-18 into IL-18−/− mice corrected their deficiencies, suggesting that these mice have Th1 cells that produce gamma interferon (IFN-γ) in response to IL-18. Indeed, these mice had normal levels of Th1 cells. Thus, IL-18 is not responsible for inducing Th1 cells but participates in host resistance by its action in stimulating Th1 cells to produce IFN-γ. Our results also indicate the high potentiality of IL-18 as a useful reagent for treatment as well as prevention against reinfection.

scholarly journals Transcriptomic Analysis of the Effect of GAT-2 Deficiency on Differentiation of Mice Naïve T Cells Into Th1 Cells In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueyan Ding ◽  
Yajie Chang ◽  
Siquan Wang ◽  
Dong Yan ◽  
Jiakui Yao ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Janus Kinase ◽  
Cell Mediated Immunity ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Bioinformatics Analyses ◽  
Naive T Cells ◽  
Naïve T Cells

The neurotransmitter γ-aminobutyric acid (GABA) is known to affect the activation and function of immune cells. This study investigated the role of GABA transporter (GAT)-2 in the differentiation of type 1 helper T (Th1) cells. Naïve CD4+ T cells isolated from splenocytes of GAT-2 knockout (KO) and wild-type (WT) mice were cultured; Th1 cell differentiation was induced and transcriptome and bioinformatics analyses were carried out. We found that GAT-2 deficiency promoted the differentiation of naïve T cells into Th1 cells. RNA sequencing revealed 2984 differentially expressed genes including 1616 that were up-regulated and 1368 that were down-regulated in GAT-2 KO cells compared to WT cells, which were associated with 950 enriched Gene Ontology terms and 33 enriched Kyoto Encyclopedia of Genes and Genomes pathways. Notably, 4 signal transduction pathways (hypoxia-inducible factor [HIF]-1, Hippo, phospholipase D, and Janus kinase [JAK]/signal transducer and activator of transcription [STAT]) and one metabolic pathway (glycolysis/gluconeogenesis) were significantly enriched by GAT-2 deficiency, suggesting that these pathways mediate the effect of GABA on T cell differentiation. Our results provide evidence for the immunomodulatory function of GABA signaling in T cell-mediated immunity and can guide future studies on the etiology and management of autoimmune diseases.

scholarly journals Tolerogenicity of resting and activated B cells.

1994 ◽  
Vol 179 (1) ◽  
pp. 249-258 ◽  
Author(s):  
K M Gilbert ◽  
W O Weigle
Keyword(s):  
B Cells ◽  
Primary Cultures ◽  
Th1 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Histocompatibility Complex ◽  
Human Gamma Globulin ◽  
Antigen Presenting ◽  
Activated B Cells

Antigen presentation by resting splenic B cells has been shown previously to induce T helper 1 cell (Th1) anergy. In contrast to expectations, it was found here that B cells treated with F(ab')2 goat anti-mouse immunoglobulin (IgM) for 24 or 48 h also presented antigen (Ag) to Th1 cells in a manner that induced dramatic Ag-specific proliferative inactivation. The tolerogenicity of the anti-Ig-treated B cells was consistent with the observation that these B cells were only slightly more efficient than resting B cells in stimulating human gamma globulin (HGG)-induced proliferation of HGG-specific Th1 cells in primary cultures. The activated B cells were, however, more efficient than resting B cells in stimulating a primary mixed leukocyte reaction, and exhibited increased expression of major histocompatibility complex class II molecules, RL388 Ag and transferrin receptor. In addition, unlike resting B cells, which expressed little detectable B7, anti-Ig-treated B cells expressed high levels of B7. The functional capacity of the B7 expressed on the activated B cells was demonstrated by the fact that the Ag-presenting capacity of these B cells was inhibited by the addition to culture of CTLA4Ig, a soluble receptor for B7. It is unlikely that the tolerogenicity of the activated B cells was due to an inability of the Th1 cells to respond to B7 signals; the Th1 clones used in the experiments, unlike the Th2 clones tested, expressed CD28, the ligand for B7. In addition, anti-CD28 monoclonal antibody inhibited the induction of Th1 cell anergy when added to cultures of Th1 cells and Ag-pulsed fixed antigen-presenting cells. Taken together, the results indicate that B cells, even when activated, do not satisfy the costimulatory requirements of the Th1 cells used here, and therefore can present Ag in a tolerogenic fashion to Th1 cells. The costimulator deficiency of activated B cells may reflect an inadequacy in the level of B7 expressed or a lack of some other molecule.

scholarly journals Listeria monocytogenes as a Short-Lived Delivery System for the Induction of Type 1 Cell-Mediated Immunity against the p36/LACK Antigen of Leishmania major

2000 ◽  
Vol 68 (3) ◽  
pp. 1498-1506 ◽  
Author(s):  
Neirouz Soussi ◽  
Geneviève Milon ◽  
Jean-Hervé Colle ◽  
Evelyne Mougneau ◽  
Nicolas Glaichenhaus ◽  
...  
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Ex Vivo ◽  
Experimental Models ◽  
Interleukin 4 ◽  
Cell Mediated Immunity ◽  
Th1 Cells ◽  
Ifn Γ

ABSTRACT Listeria monocytogenes has been used as an experimental live vector for the induction of CD8-mediated immune responses in various viral and tumoral experimental models. Susceptibility of BALB/c mice to Leishmania major infection has been correlated to the preferential development of Th2 CD4 T cells through an early production of interleukin 4 (IL-4) by a restricted population of CD4 T cells which react to a single parasite antigen, LACK (stands forLeishmania homologue of receptors for activated C kinase). Experimental vaccination with LACK can redirect the differentiation of CD4+ T cells towards the Th1 pathway if LACK is coadministrated with IL-12. As IL-12 is known to be induced by L. monocytogenes, we have tested the ability of a recombinant attenuated actA mutant L. monocytogenes strain expressing LACK to induce the development of LACK-specific Th1 cells in both B10.D2 and BALB/c mice, which are resistant and susceptible toL. major, respectively. After a single injection of LACK-expressing L. monocytogenes, IL-12/p40 transcripts showed a rapid burst, and peaks of gamma interferon (IFN-γ)-secreting LACK-specific Th1 cells were detected around day 5 in the spleens and livers of mice of both strains. These primed IFN-γ-secreting LACK-reactive T cells were not detected ex vivo after day 7 of immunization but could be recruited and detected 15 days later in the draining lymph node after an L. major footpad challenge. Although immunization of BALB/c mice with LACK-expressing L. monocytogenes did not change the course of the infection withL. major, immunized B10.D2 mice exhibited significantly smaller lesions than nonimmunized controls. Thus, our results demonstrate that, in addition of its recognized use for the induction of effector CD8 T cells, L. monocytogenes can also be used as a live recombinant vector to favor the development of potentially protective IFN-γ-secreting Th1 CD4 T lymphocytes.

scholarly journals Conditions Influencing the Efficacy of Vaccination with Live Organisms against Leishmania major Infection

2005 ◽  
Vol 73 (8) ◽  
pp. 4714-4722 ◽  
Author(s):  
Khaled S. Tabbara ◽  
Nathan C. Peters ◽  
Farhat Afrin ◽  
Susana Mendez ◽  
Sylvie Bertholet ◽  
...  
Keyword(s):  
T Cells ◽  
Leishmania Major ◽  
Parasite Clearance ◽  
Interleukin 10 ◽  
Secondary Site ◽  
Cell Mediated Immunity ◽  
Intradermal Vaccination ◽  
Successful Vaccine ◽  
Ifn Γ ◽  
Strength And Durability

ABSTRACT Numerous experimental vaccines have been developed with the goal of generating long-term cell-mediated immunity to the obligate intracellular parasite Leishmania major, yet inoculation with live, wild-type L. major remains the only successful vaccine in humans. We examined the expression of immunity at the site of secondary, low-dose challenge in the ear dermis to determine the kinetics of parasite clearance and the early events associated with the protection conferred by vaccination with live L. major organisms in C57BL/6 mice. Particular attention was given to the route of vaccination. We observed that the rapidity, strength, and durability of the memory response following subcutaneous vaccination with live parasites in the footpad are even greater than previously appreciated. Antigen-specific gamma interferon (IFN-γ)-producing T cells infiltrate the secondary site by 1.5 weeks, and viable parasites are cleared as early as 2.5 weeks following rechallenge, followed by a rapid drop in IFN-γ+ CD4+ cell numbers in the site. In comparison, intradermal vaccination with live parasites in the ear generates immunity that is delayed in effector cell recruitment to the rechallenge site and in the clearance of parasites from the site. This compromised immunity was associated with a rapid recruitment of interleukin-10 (IL-10)-producing CD4+ T cells to the rechallenge site. Treatment with anti-IL-10-receptor or anti-CD25 antibody enhanced early parasite clearance in ear-vaccinated mice, indicating that chronic infection in the skin generates a population of regulatory cells capable of influencing the level of resistance to reinfection. A delicate balance of effector and regulatory T cells may be required to optimize the potency and durability of vaccines against Leishmaniasis and other intracellular pathogens.

scholarly journals Imbalance between T helper 1 and regulatory T cells plays a detrimental role in experimental Parkinson’s disease in mice

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052199847
Author(s):  
Wenjie Li ◽  
Yuan Luo ◽  
Hongyu Xu ◽  
Qianqian Ma ◽  
Qi Yao
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Treg Cell ◽  
Neutralizing Antibodies ◽  
Treg Cells ◽  
Th1 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Degenerative Disorder

Objective Parkinson’s disease (PD) is a degenerative disorder characterized by steady motor function loss. PD pathogenesis remains inconclusive, but aberrant immune responses might play important roles. We hypothesized that imbalance between T helper (Th) 1 and regulatory T (Treg) cells was essential in experimental PD. Methods Th1 and Treg cells from the blood of patients with PD and healthy volunteer blood were measured by flow cytometry. Experimental PD was induced in mice by peritoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Experimental PD severity was measured by open field test behavior assessments (distance moved, rearing, and grooming). Mice were administered neutralizing anti-tumor necrosis factor (TNF) α to inhibit Th1 effects. Treg cells were depleted by anti-CD25 neutralizing antibodies or isolated and transferred to experimental PD mice. Results Patients with PD had fewer Treg and more Th1 cells than healthy volunteers. Experimental PD mice exhibited fewer Treg and more Th1 cells. Treg cell depletion exacerbated experimental PD, whereas TNFα neutralization attenuated PD in mice. Treg transfer to experimental PD mice reduced PD severity. Mechanistically, anti-TNFα antibody administration and Treg transfer increased Treg and reduced Th1 cell abundance in the brain. Conclusion Th1 and Treg cell imbalance plays an essential role in mouse experimental PD pathogenesis.

scholarly journals A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3867-3873 ◽  
Author(s):  
Greg H. Underhill ◽  
Dimitrios G. Zisoulis ◽  
K. Pallav Kolli ◽  
Lesley G. Ellies ◽  
Jamey D. Marth ◽  
...  
Keyword(s):  
Interleukin 12 ◽  
Th1 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Selectin Ligands ◽  
Ligand Expression ◽  
Selectin Ligand ◽  
Carbohydrate Ligands ◽  
Transcriptional Pathway

Proinflammatory T helper 1 (Th1) cells express high levels of carbohydrate ligands for the endothelial selectins, but the molecular basis for this phenotype is incompletely understood. We document here a significant role in selectin ligand formation for the recently described Th1 transcription factor T-bet. Th1 cells generated from T-bet-/- mice showed significantly lower levels of ligands for both E-selectin and P-selectin, compared with wild-type (WT) Th1 cells. Enforced expression of T-bet in WT Th0 cells only modestly up-regulated P-selectin ligands and had no effect on E-selectin ligands. To define a mechanism for the defects observed in T-bet-/- mice, we examined expression of glycosyltransferases involved in selectin ligand biosynthesis. T-bet-/- Th1 cells expressed significantly lower levels of core 2 β1,6 N-acetylglucosaminyltransferase I (C2GlcNAcT-I), but no differences in levels of α 2,3-sialyltransferase IV (ST3Gal-IV). Further, we show that T-bet is responsible for the signal transducer and activator of transcription 4 (Stat4)–independent increase in Th1 cells of fucosyltransferase VII (FucT-VII). We also identify ST3Gal-VI, which is thought to play an important role in E- and P-selectin ligand formation, as an interleukin 12 (IL-12)–regulated, T-bet–dependent gene. These data show that T-bet controls selectin ligand formation in Th1 cells via control of expression of multiple key enzymes in response to IL-12 signaling and establishes an independent transcriptional pathway for control of Th1 cell traffic.

scholarly journals CD4+CD25−Foxp3− Th1 cells are the source of IL-10–mediated immune suppression in chronic cutaneous leishmaniasis

2007 ◽  
Vol 204 (2) ◽  
pp. 285-297 ◽  
Author(s):  
Charles F. Anderson ◽  
Mohammed Oukka ◽  
Vijay J. Kuchroo ◽  
David Sacks
Keyword(s):  
T Cells ◽  
Immune Suppression ◽  
Leishmania Major ◽  
T Regulatory Cells ◽  
Th1 Cells ◽  
Chronic Infections ◽  
Th1 Cell ◽  
Relative Contribution ◽  
Severe Infections

Nonhealing forms of leishmaniasis in humans are commonly associated with elevated levels of the deactivating cytokine IL-10, and in the mouse, normally chronic infections can be cleared in the absence of IL-10. Using a Leishmania major strain that produces nonhealing dermal lesions in a T helper type 1 (Th1) cell–polarized setting, we have analyzed the cellular sources of IL-10 and their relative contribution to immune suppression. IL-10 was produced by innate cells, as well as CD4+CD25+Foxp3+ and CD4+CD25−Foxp3− T cells in the chronic lesion. Nonetheless, only IL-10 production by antigen-specific CD4+CD25−Foxp3− T cells, the majority of which also produced IFN-γ, was necessary for suppression of acquired immunity in Rag−/− reconstituted mice. Surprisingly, Rag−/− mice reconstituted with naive CD4+ T cells depleted of natural T regulatory cells developed more severe infections, associated with elevated levels of IL-10 and, especially, Th2 cytokines in the site. The data demonstrate that IL-10–producing Th1 cells, activated early in a strong inflammatory setting as a mechanism of feedback control, are the principal mediators of T cell–derived IL-10–dependent immune suppression in a chronic intracellular infection.

scholarly journals Stress-Inducible Gene Atf3 Dictates a Dichotomous Macrophage Activity in Chemotherapy-Enhanced Lung Colonization

2021 ◽  
Vol 22 (14) ◽  
pp. 7356
Author(s):  
Justin D. Middleton ◽  
Jared Fehlman ◽  
Subhakeertana Sivakumar ◽  
Daniel G. Stover ◽  
Tsonwin Hai
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Early Stage ◽  
Mechanistic Explanation ◽  
Host Cells ◽  
Secondary Site ◽  
Initial Increase ◽  
Cell Retention ◽  
Lung Colonization ◽  
Inducible Gene

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization—despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.

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