scholarly journals Sexual Dimorphism in the Control of Amebic Liver Abscess in a Mouse Model of Disease

2006 ◽  
Vol 74 (1) ◽  
pp. 118-124 ◽  
Author(s):  
Hannelore Lotter ◽  
Thomas Jacobs ◽  
Iris Gaworski ◽  
Egbert Tannich
Keyword(s):  
T Cells ◽  
Sexual Dimorphism ◽  
Liver Abscess ◽  
Cytokine Production ◽  
Experimental Studies ◽  
Nkt Cells ◽  
Amebic Liver Abscess ◽  
Male Mice ◽  
Female Mice ◽  
Ifn Γ

ABSTRACT Amebic liver abscess (ALA) is the most common extraintestinal manifestation of human infection by the enteric protozoan parasite Entamoeba histolytica. In contrast to intestinal infection, ALA greatly predominates in males but is rare in females. Since humans are the only relevant host for E. histolytica, experimental studies concerning this sexual dimorphism have been hampered by the lack of a suitable animal model. By serial liver passage of cultured E. histolytica trophozoites in gerbils and mice, we generated amebae which reproducibly induce ALA in C57BL/6 mice. Interestingly, all animals developed ALA, but the time courses of abscess formation differed significantly between the genders. Female mice were able to clear the infection within 3 days, whereas in male mice the parasite could be recovered for at least 14 days. Accordingly, male mice showed a prolonged time of recovery from ALA. Immunohistology of abscesses revealed that polymorphonuclear leukocytes and macrophages were the dominant infiltrates, but in addition, γ,δ-T cells, NK cells, and natural killer T (NKT) cells were also present at early times during abscess development, whereas conventional α,β-T cells appeared later, when female mice had already cleared the parasite. Interestingly, male and female mice differed in early cytokine production in response to ameba infection. Enzyme-linked immunospot assays performed with spleen cells of infected animals revealed significantly higher numbers of interleukin-4-producing cells in male mice but significantly higher numbers of gamma interferon (IFN-γ)-producing cells in female mice. Early IFN-γ production and the presence of functional NKT cells were found to be important for the control of hepatic amebiasis as application of an IFN-γ-neutralizing monoclonal antibody or the use of NKT knockout mice (Vα14iNKT, Jα 18−/−) dramatically increased the size of ALA in female mice. In addition, E. histolytica trophozoites could be reisolated from liver abscesses of Jα18−/− mice on day 7 postinfection, when wild-type mice had already cleared the parasite. These data suggest that the sexual dimorphism in the control of ALA is due to gender-specific differences in early cytokine production mediated at least in part by NKT cells in response to E. histolytica infection of the liver.

Abstract 113: Regulatory T Cells Contribute to Sexual Dimorphic Outcomes After Acute Ischemic Brain Injury

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Zeyu Sun ◽  
Wei Su ◽  
Ligen Shi ◽  
Jie Chen ◽  
Xiaoming Hu
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cell ◽  
Infarct Volume ◽  
Young Male ◽  
Young Female ◽  
Male Mice ◽  
Stroke Outcomes ◽  
Female Mice ◽  
Ifn Γ

Introduction: The contribution of CD4 + Foxp3 + regulatory T cells (Treg) to acute stroke outcomes has been controversially reported in young male murine models of stroke, their effects in female stroke mice, however, are not characterized. This study explored the sexual dimorphisms in Treg and its contribution to acute stroke outcomes. Methods: Cerebral ischemia was induced by 60 min tMCAO in male or female (Young: 10-week, aged: 15-month) wild type (WT) mice and DTR mice expressing the diphtheria toxin (DT) receptor under the control of Foxp3 promoter. Tregs depletion was achieved by DT injection in DTR mice for 3 days prior to tMCAO. Infarct volume, sensorimotor functions and peripheral immune cell populations were assessed up to 5d after stroke. For RNA sequencing analysis, Tregs were sorted from blood of male or female DTR mice at 5d after sham or tMCAO surgery. Results: Young Treg competent (WT mice or DTR mice without DT) female mice exhibited significantly reduced infarct volume, as assessed by MRI T2 scanning and MAP2 staining, and greatly improved sensorimotor functions (rotarod test and adhesive removal test) compared to age- and genotype-matched male mice (n=8/group) 5d after tMCAO. Treg depletion deprived the neuroprotection in young female, while showed no significant effect on young male or aged female mice (n=8/group). RNA-seq analysis showed that IFN-γ signaling was downregulated in female Treg while upregulated in male Treg, suggesting a sexual difference in Treg-mediated immune response after stroke. Flow cytometry revealed ameliorated immune cell activation in blood and brain in female vs male mice 5d after stroke. Furthermore, Treg were isolated from young female, young male, aged female or female mice subjected to ovariectomy, and adoptively transferred (1 million cell/animal, iv) to young male mice 1 hour after tMCAO. Only young female Treg significantly reduced the infarct volume and improved sensorimotor functions compared to other treatment groups (n=7-8/group). Conclusion: Treg contribute to the neuroprotection in young female vs male in an age- and hormone-dependent manner. Transcriptomic analysis uncovered sexual differences in an IFN-γ centered regulatory pathways in Tregs, which keep post-stroke immune responses in check.

scholarly journals Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8+ T cells

2017 ◽  
Vol 114 (36) ◽  
pp. 9677-9682 ◽  
Author(s):  
Fiamma Salerno ◽  
Nahuel A. Paolini ◽  
Regina Stark ◽  
Marieke von Lindern ◽  
Monika C. Wolkers
Keyword(s):  
T Cells ◽  
Mrna Stability ◽  
Cytokine Production ◽  
De Novo ◽  
Translation Efficiency ◽  
Mrna Stabilization ◽  
Relative Contribution ◽  
Production Kinetics ◽  
Tnf Α ◽  
Ifn Γ

Effective T cell responses against invading pathogens require the concerted production of three key cytokines: TNF-α, IFN-γ, and IL-2. The cytokines functionally synergize, but their production kinetics widely differ. How the differential timing of expression is regulated remains, however, poorly understood. We compared the relative contribution of transcription, mRNA stability, and translation efficiency on cytokine production in murine effector and memory CD8+ T cells. We show that the immediate and ample production of TNF-α is primarily mediated by translation of preformed mRNA through protein kinase C (PKC)-induced recruitment of mRNA to polyribosomes. Also, the initial production of IFN-γ uses translation of preformed mRNA. However, the magnitude and subsequent expression of IFN-γ, and of IL-2, depends on calcium-induced de novo transcription and PKC-dependent mRNA stabilization. In conclusion, PKC signaling modulates translation efficiency and mRNA stability in a transcript-specific manner. These cytokine-specific regulatory mechanisms guarantee that T cells produce ample amounts of cytokines shortly upon activation and for a limited time.

scholarly journals CXCL12-CXCR4-Mediated Chemotaxis Supports Accumulation of Mucosal-Associated Invariant T Cells Into the Liver of Patients With PBC

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhilei Chen ◽  
Suying Liu ◽  
Chengmei He ◽  
Jinlei Sun ◽  
Li Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Cytokine Production ◽  
Immunofluorescence Staining ◽  
Primary Biliary Cholangitis ◽  
Hepatic Hemangioma ◽  
Cxcr4 Antagonist ◽  
Mait Cells ◽  
Ifn Γ ◽  
Invariant T Cells

Objectives: To explore the potential role of CD3+CD8+CD161high TCRVα7.2+ mucosal-associated invariant T (MAIT) cells in the pathogenesis of primary biliary cholangitis (PBC).Methods: We enrolled 55 patients with PBC, 69 healthy controls (HCs), and 8 patients with hepatic hemangioma. Circulating MAIT cells and their chemokine receptor profiles and cytokine production were quantified using flow cytometry. Liver-resident MAIT cells were examined by immunofluorescence staining. CXCL12-mediated chemotaxis of MAIT cells was measured using a transwell migration assay. Plasma interleukin (IL)-18 was measured using ELISA, and cytokine production in IL-18-stimulated MAIT cells was detected using flow cytometry.Result: Peripheral MAIT cells were found to be significantly lower in patients with PBC (3.0 ± 3.2% vs. 9.4 ± 8.0%, p < 0.01) and negatively correlated with alkaline phosphatase (ALP) levels (r = −0.3209, p < 0.05). Liver immunofluorescence staining suggested that MAIT cells might accumulate in PBC liver. MAIT cells from patients with PBC expressed higher levels of CXCR4 (84.8 ± 18.0% vs. 58.7 ± 11.4%, p < 0.01), and the expression of CXCL12 was higher in PBC liver. CXCL12 promoted MAIT cell chemotaxis (70.4 ± 6.8% vs. 52.2 ± 3.5%, p < 0.01), which was attenuated by CXCR4 antagonist. MAIT cells from PBC produced significantly more interferon-γ (IFN-γ) (88.3 ± 4.2% vs. 64.2 ± 10.1%, p < 0.01), tumor necrosis factor-α (TNF-α) (93.0 ± 1.1% vs. 80.1 ± 5.3%, p < 0.01), Granzyme B (89.3 ± 3.3% vs. 72.1 ± 7.0%, p < 0.01), and perforin (46.8 ± 6.6% vs. 34.8 ± 7.7%, p < 0.05). MAIT cells from PBC expressed higher levels of IL18-Rα (83.8 ± 10.2% vs. 58.3 ± 8.7%, p < 0.01). Plasma IL-18 was more abundant in patients with PBC (286.8 ± 75.7 pg/ml vs. 132.9 ± 78.1 pg/ml, p < 0.01). IL-18 promoted IFN-γ production in MAIT cells (74.9 ± 6.6% vs. 54.7 ± 6.7%, p < 0.01), which was partially attenuated by blocking IL-18R (68.6 ± 8.3% vs. 43.5 ± 4.2%, p < 0.01).Conclusion: Mucosal-associated invariant T cells from patients with PBC accumulated in the liver via CXCL12-CXCR4-mediated chemotaxis, produced pro-inflammatory cytokines, and contributed to portal inflammation, which was potentially mediated by elevated IL-18. Targeting MAIT cells might be a therapeutic approach for PBC.

scholarly journals Cytolethal Distending Toxin Is Essential for Helicobacter hepaticus Colonization in Outbred Swiss Webster Mice

2005 ◽  
Vol 73 (6) ◽  
pp. 3559-3567 ◽  
Author(s):  
Zhongming Ge ◽  
Yan Feng ◽  
Mark T. Whary ◽  
Prashant R. Nambiar ◽  
Shilu Xu ◽  
...  
Keyword(s):  
Mrna Level ◽  
Interleukin 10 ◽  
Mouse Strains ◽  
Cytolethal Distending Toxin ◽  
Mrna Levels ◽  
Helicobacter Hepaticus ◽  
Male Mice ◽  
Susceptible Mouse ◽  
Female Mice ◽  
Ifn Γ

ABSTRACT Helicobacter hepaticus, which induces chronic hepatitis and typhlocolitis in susceptible mouse strains, produces a cytolethal distending toxin (CDT) consisting of CdtA, CdtB, and CdtC. A cdtB-deficient H. hepaticus isogenic mutant (HhcdtBm7) was generated and characterized for colonization parameters in four intestinal regions (jejunum, ileum, cecum, and colon) of outbred Swiss Webster (SW) mice. Inactivation of the cdtB gene abolished the ability of HhcdtBm7 to colonize female mice at both 8 and 16 weeks postinfection (wpi), whereas HhcdtBm7 colonized all of four intestinal regions of three of five males at 8 wpi and then was eliminated by 16 wpi. Wild-type (WT) H. hepaticus was detected in the corresponding intestinal regions of both male and female mice at 8 and 16 wpi; however, colonization levels of WT H. hepaticus in the cecum and colon of male mice were approximately 1,000-fold higher than in females (P < 0.0079) at 16 wpi. Infection with WT H. hepaticus, but not HhcdtBm7, at 8 wpi was associated with significantly increased mRNA level of ileal and cecal gamma interferon (IFN-γ) in females (P < 0.016 and 0.031 between WT H. hepaticus-infected and sham-dosed females, respectively). In contrast, the mRNA levels of IFN-γ were significantly higher in the colon (P < 0.0079) and trended to be higher in the cecum (P < 0.15) in the HhcdtBm7-colonized male mice versus the sham-dosed controls at 8 wpi. In addition, mRNA levels of ileal IFN-γ were significantly higher in the control females than males at 8 wpi (P < 0.016). There were significantly higher Th1-associated immunoglobulin G2a (IgG2a), Th2-associated IgG1 and mucosal IgA (P < 0.002, 0.002, 0.002, respectively) responses in the mice infected with WT H. hepaticus when compared to HhcdtBm7 at 16 wpi. Colonic interleukin-10 (IL-10) expressions at 16 wpi were significantly lower in both female and male mice colonized by WT H. hepaticus or in males transiently colonized through 8 wpi by HhcdtBm7 versus control mice (P < 0.0159). These lines of evidence indicate that (i) H. hepaticus CDT plays a crucial role in the persistent colonization of H. hepaticus in SW mice; (ii) SW female mice are more resistant to H. hepaticus colonization than male mice; (iii) there was persistent colonization of WT H. hepaticus in cecum, colon, and jejunum but only transient colonization of H. hepaticus in the ileum of female mice; (iv) H. hepaticus colonization was associated with down-regulation of colonic IL-10 production.

scholarly journals PD-1+ Tim3+ tumor-infiltrating CD8 T cells sustain the potential for IFN-γ production, but lose cytotoxic activity in ovarian cancer

2020 ◽  
Vol 32 (6) ◽  
pp. 397-405 ◽  
Author(s):  
Masaaki Sawada ◽  
Kumiko Goto ◽  
Akiko Morimoto-Okazawa ◽  
Miya Haruna ◽  
Kei Yamamoto ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Poor Prognosis ◽  
Tumor Antigens ◽  
Cytokine Production ◽  
Intracellular Cytokine Staining ◽  
Target Cell Line ◽  
Direct Cytotoxicity ◽  
Membrane Bound ◽  
Ifn Γ

Abstract Persistent exposure to tumor antigens results in exhausted tumor-infiltrating T cells (TILs) that express the immune checkpoint molecules, PD-1 and Tim3, and lack anti-tumor immunity. To examine the exhausted status of TILs in ovarian cancer, the potential for cytokine production, proliferation and cytotoxicity by purified PD-1+ Tim3+ CD8 TILs was assessed. The production of IFN-γ and TNF-α by PD-1+ Tim3+ CD8 TILs remained the same in an intracellular cytokine staining assay and was higher in a cytokine catch assay than that by PD-1− Tim3− and PD-1+ Tim3− CD8 TILs. %Ki67+ was higher in PD-1+ Tim3+ CD8 TILs than in PD-1− Tim3− CD8 TILs. However, patients with high PD-1+ Tim3+ CD8 TILs had a poor prognosis. The potential for cytotoxicity was then examined. %Perforin+ and %granzyme B+ were lower in PD-1+ Tim3+ CD8 TILs than in PD-1− Tim3− and PD-1+ Tim3− CD8 TILs. To observe the potential for direct cytotoxicity by T cells, a target cell line expressing membrane-bound anti-CD3scFv was newly established and a cytotoxic assay targeting these cells was performed. The cytotoxicity of PD-1+ Tim3+ CD8 TILs was significantly lower than that of PD-1− Tim3− and PD-1+ Tim3− CD8 TILs. Even though PD-1+ Tim3+ CD8 TILs in ovarian cancer showed a sustained potential for cytokine production and proliferation, cytotoxicity was markedly impaired, which may contribute to the poor prognosis of patients with ovarian cancer. Among the impaired functions of exhausted TILs, cytotoxicity may be an essential target for cancer immunotherapy.

scholarly journals Invariant Vα14 Chain NKT Cells Promote Plasmodium berghei Circumsporozoite Protein-Specific Gamma Interferon- and Tumor Necrosis Factor Alpha-Producing CD8+ T Cells in the Liver after Poxvirus Vaccination of Mice

2005 ◽  
Vol 73 (2) ◽  
pp. 849-858 ◽  
Author(s):  
Simone Korten ◽  
Richard J. Anderson ◽  
Carolyn M. Hannan ◽  
Eric G. Sheu ◽  
Robert Sinden ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Plasmodium Berghei ◽  
Tumor Necrosis ◽  
Nkt Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Understanding the protective mechanism in the liver induced by recombinant vaccines against the pre-erythrocytic stages of malaria is important for vaccine development. Most studies in mice have focused on splenic and peripheral blood T cells and identified gamma interferon (IFN-γ)-producing CD8+ T cells as correlates of protection, which can be induced by prime-boost vaccination with recombinant poxviruses. Invariant natural killer T (Vα14iNKT) cells can also protect against liver stage malaria, when activated, and are abundant in the liver. Since poxviruses have nonspecific immunomodulating effects, which are incompletely understood, we investigated whether recombinant poxviruses affect the protective properties of hepatic Vα14iNKT cells and thus vaccine efficacy. We show that intradermal vaccination with recombinant poxviruses activated Vα14iNKT cells and NK cells in the livers of BALB/c mice while inducing IFN-γ- and tumor necrosis factor alpha (TNF-α)-producing pre-erythrocytic stage antigen-specific CD8+ T cells. Greater numbers of hepatic Vα14iNKT cells secreted interleukin-4 than IFN-γ. Vaccinated Vα14iNKT-cell-deficient mice had lower, but still protective levels of hepatic and splenic IFN-γ+ and TNF-α+ CD8+ T cells and better protection rates later after challenge with Plasmodium berghei sporozoites. Therefore, vaccine-activated hepatic Vα14iNKT cells help in generating specific T cells but are not required for protection induced by recombinant poxviruses. Furthermore, double-positive INF-γ+/TNF-α+ CD8+ T cells were enriched in protected livers, suggesting that cells expressing both of these cytokines may be most relevant for protection.

Salutary effects of 17β-estradiol on T-cell signaling and cytokine production after trauma-hemorrhage are mediated primarily via estrogen receptor-α

2007 ◽  
Vol 292 (6) ◽  
pp. C2103-C2111 ◽  
Author(s):  
Takao Suzuki ◽  
Tomoharu Shimizu ◽  
Huang-Ping Yu ◽  
Ya-Ching Hsieh ◽  
Mashkoor A. Choudhry ◽  
...  
Keyword(s):  
T Cells ◽  
Estrogen Receptor ◽  
T Cell ◽  
Signaling Pathways ◽  
Cytokine Production ◽  
Estrogen Receptor Α ◽  
Male Rats ◽  
17Β Estradiol ◽  
Ifn Γ ◽  
Cell Cytokine Production

Although 17β-estradiol (E2) administration following trauma-hemorrhage prevents the suppression in splenocyte cytokine production, it remains unknown whether the salutary effects of 17β-estradiol are mediated via estrogen receptor (ER)-α or ER-β. Moreover, it is unknown which signaling pathways are involved in 17β-estradiol's salutary effects. Utilizing an ER-α- or ER-β-specific agonist, we examined the role of ER-α and ER-β in E2-mediated restoration of T-cell cytokine production following trauma-hemorrhage. Moreover, since MAPK, NF-κB, and activator protein (AP)-1 are known to regulate T-cell cytokine production, we also examined the activation of MAPK, NF-κB, and AP-1. Male rats underwent trauma-hemorrhage (mean arterial pressure 40 mmHg for 90 min) and fluid resuscitation. ER-α agonist propyl pyrazole triol (PPT; 5 μg/kg), ER-β agonist diarylpropionitrile (DPN; 5 μg/kg), 17β-estradiol (50 μg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic T cells were isolated, and their IL-2 and IFN-γ production and MAPK, NF-κB, and AP-1 activation were measured. T-cell IL-2 and IFN-γ production was decreased following trauma-hemorrhage, and this was accompanied with a decrease in T-cell MAPK, NF-κB, and AP-1 activation. PPT or 17β-estradiol administration following trauma-hemorrhage normalized those parameters, while DPN administration had no effect. Since PPT, but not DPN, administration following trauma-hemorrhage was as effective as 17β-estradiol in preventing the T-cell suppression, it appears that ER-α plays a predominant role in mediating the salutary effects of 17β-estradiol on T cells following trauma-hemorrhage, and that such effects are likely mediated via normalization of MAPK, NF-κB, and AP-1 signaling pathways.

scholarly journals Gonadal Steroids Negatively Modulate Oxidative Stress in CBA/Ca Female Mice Infected withP. bergheiANKA

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Néstor Aarón Mosqueda-Romo ◽  
Ana Laura Rodríguez-Morales ◽  
Fidel Orlando Buendía-González ◽  
Margarita Aguilar-Sánchez ◽  
Jorge Morales-Montor ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Superoxide Dismutase ◽  
Sexual Dimorphism ◽  
Stress Response ◽  
Glutathione Peroxidase ◽  
Oxidative Stress Response ◽  
Gonadal Steroids ◽  
Male Mice ◽  
Female Mice

We decreased the level of gonadal steroids in female and male mice by gonadectomy. We infected these mice withP. bergheiANKA and observed the subsequent impact on the oxidative stress response. Intact females developed lower levels of parasitaemia and lost weight faster than intact males. Gonadectomised female mice displayed increased levels of parasitaemia, increased body mass, and increased anaemia compared with their male counterparts. In addition, gonadectomised females exhibited lower specific catalase, superoxide dismutase, and glutathione peroxidase activities in their blood and spleen tissues compared with gonadectomised males. To further study the oxidative stress response inP. bergheiANKA-infected gonadectomised mice, nitric oxide levels were assessed in the blood and spleen, and MDA levels were assessed in the spleen. Intact, sham-operated, and gonadectomised female mice exhibited higher levels of nitric oxide in the blood and spleen compared with male mice. MDA levels were higher in all of the female groups. Finally, gonadectomy significantly increased the oxidative stress levels in females but not in males. These data suggest that differential oxidative stress is influenced by oestrogens that may contribute to sexual dimorphism in malaria.

scholarly journals Mechanism of Reduced T-Cell Effector Functions and Class-Switched Antibody Responses to Herpes Simplex Virus Type 2 in the Absence of B7 Costimulation

2003 ◽  
Vol 77 (4) ◽  
pp. 2426-2435 ◽  
Author(s):  
Lydia G. Thebeau ◽  
Lynda A. Morrison
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
Antibody Responses ◽  
Wild Type ◽  
Effector Functions ◽  
Lymphocyte Activity ◽  
Ifn Γ ◽  
Simplex Virus

ABSTRACT T-cell costimulation molecules B7-1 and B7-2 play an important role in activation of T cells to cytolytic effector function and production of cytokines. Interaction with B7 also causes T cells to upregulate surface molecules, such as CD40L, that effectively stimulate antibody responses in conjunction with cytokines. We have shown that mice lacking both B7-1 and B7-2 (B7KO mice), when infected intravaginally with virulent herpes simplex virus type 2 (HSV-2), developed more severe disease and higher mortality than their wild-type counterparts. We have now investigated the effects of B7 costimulation deficiency on induction of immune responses to HSV-2 infection of the genital tract. Fewer gamma interferon (IFN-γ)-producing T cells were present in the genital lymph nodes of B7KO mice compared to wild-type mice, either acutely after primary infection or in recall responses. Less IFN-γ and especially interleukin-10 were produced by B7KO mice, and cytolytic T-lymphocyte activity was also attenuated. Reduced expression of CD25 on CD4+ T cells after infection of B7KO mice was consistent with deficits in T-cell activation to effector functions. Although HSV-specific immunoglobulin M (IgM) titers were comparable for both B7KO mice and wild-type mice, B7KO mice had significant deficits in HSV-specific serum IgG responses, with markedly reduced levels of IgG2a and IgG1. In addition, significantly less IgG was detected in the vaginal secretions of B7KO mice than in those from wild-type mice. CD4+ T-cell expression of CD40L was depressed in B7KO mice in vivo and in vitro. Together with reduced cytokine production, these results suggest a mechanism for decreased IgG class switching or production. Thus, in the absence of B7 costimulation, naïve T cells fail to undergo proper activation in response to HSV-2, which limits T-cell cytokine production, cytotoxic T lymphocyte activity, and provision of help for class-switched antibody responses.

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