scholarly journals CXCR3 Deficiency Increases Susceptibility to Genital Herpes Simplex Virus Type 2 Infection: Uncoupling of CD8+ T-Cell Effector Function but Not Migration

2009 ◽  
Vol 83 (18) ◽  
pp. 9486-9501 ◽  
Author(s):  
Manoj Thapa ◽  
Daniel J. J. Carr
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Viral Infection ◽  
Genital Herpes ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus

ABSTRACT CXCR3 is a G-protein-coupled receptor preferentially expressed by activated T cells, NK cells, and dendritic cells. Signaling through gamma interferon-regulated chemokines CXCL9, CXCL10, CXCL11, and CXCR3 plays a critical role in the immune response of many viral pathogens. However, the relevance of CXCR3 for optimal T-cell activation and the induction of regulatory transcription factors (i.e., T-bet and eomesodermin) relative to host immune defense against genital herpes simplex virus type 2 (HSV-2) infection have been poorly defined. In this study, we evaluated the requirement of CXCR3 expression during genital HSV-2 infection using mice deficient in CXCR3 (CXCR3−/−) along with wild-type (WT) controls, assessing the resistance of mice to viral infection and focusing on the cytokine/chemokine response, phenotypic analysis of recruited leukocytes, and functional analysis of CD8+ T cells. CXCR3−/− mice showed a heightened sensitivity to infection compared to WT animals in terms of the viral burden in infected tissues as well as elevated mortality. The poor response of CXCR3−/− mice to viral infection was associated with reduced cytotoxic T-lymphocyte activity through the impairment of T-bet, perforin, and granzyme B expression by CD8+ T cells. Corresponding with the defective cytolytic activity, a reduction in recruitment of plasmacytoid dendritic cells and CD80 expression in CD11c+ dendritic cells in the draining lymph nodes of CXCR3−/− mice were detected. Collectively, the results provide a new perspective to CXCR3 signaling for the appropriate activation of CD8+ T cells required for host defense against genital HSV-2 infection.

scholarly journals Diversity of the CD8+ T-Cell Response to Herpes Simplex Virus Type 2 Proteins among Persons with Genital Herpes

2006 ◽  
Vol 80 (11) ◽  
pp. 5509-5515 ◽  
Author(s):  
Nancy Hosken ◽  
Patrick McGowan ◽  
Amalia Meier ◽  
David M. Koelle ◽  
Paul Sleath ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Cell Response ◽  
T Cell Response ◽  
Simplex Virus

ABSTRACT Cytolytic T cells play a major role in controlling herpes simplex virus type 2 (HSV-2) infections in humans. In an effort to more thoroughly evaluate the response to HSV-2 directly, ex vivo, we developed an enzyme-linked immunospot (ELISPOT) assay that utilized pools of overlapping synthetic peptides presented by autologous dendritic cells to purified CD8+ T cells. Donor response rates to individual open reading frames (ORFs) ranged from fewer than 5% responding to as many as 70% responding, with the greatest frequency of responses (by ORF) being directed against UL39, UL25, UL27, ICP0, UL46, and UL47 in descending order of frequency. HSV-2-seropositive subjects responded to as few as 3 or as many as 46 of the 48 ORFs tested, with a median of 11 ORFs recognized. HLA-B*07 expression correlated with stronger responses overall that were directed primarily against UL49 and UL46. Cumulative precursor frequencies in the blood ranged from 500 to almost 6,000 HSV-2 spot-forming units/106 CD8+ T cells. The magnitude and breadth of the response in the infected population were greater than previously appreciated. Whether this variability in the CD8+ T-cell response within individuals is associated with the frequency of viral reactivation warrants further study.

T-cell-mediated mechanisms involved in resolution of genital herpes simplex virus type 2 (HSV-2) infection of mice

2004 ◽  
Vol 61 (2) ◽  
pp. 115-127 ◽  
Author(s):  
Gregg N. Milligan ◽  
Kristen L. Dudley-McClain ◽  
Christal G. Young ◽  
Chin-Fun Chu
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Genital Herpes ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus

scholarly journals Differential roles of B cells and IFN-γ-secreting CD4+ T cells in innate and adaptive immune control of genital herpes simplex virus type 2 infection in mice

2001 ◽  
Vol 82 (4) ◽  
pp. 845-853 ◽  
Author(s):  
Ali M. Harandi ◽  
Bo Svennerholm ◽  
Jan Holmgren ◽  
Kristina Eriksson
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
B Cells ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Ifn Γ ◽  
Simplex Virus

The role of B, CD4+ T and CD8+ T cells in both primary genital infection with attenuated herpes simplex virus type 2 (HSV-2) and development of protective immunity to a later challenge with virulent HSV-2 using lymphocyte-deficient mice has been elucidated. Following primary inoculation with attenuated thymidine kinase-deficient (TK−) HSV-2, B cell-deficient (μMT) mice developed a local viraemia and transient genital inflammation, suggesting a role for B cells in the innate control of local infection and inflammation. Natural antibodies are implicated in this process, as passive transfer of normal serum into μMT mice significantly reduced HSV-2 TK− shedding in the vaginal lumen, although it did not affect subsequent inflammation. Protection against lethal HSV-2 challenge was noted in HSV-2-vaccinated wild-type, CD8+ T cell-deficient and μMT mice and was characterized by strong virus-specific IFN-γ responses in vitro and delayed type hypersensitivity (DTH) responses in vivo. In contrast, CD4+ T cell-deficient (CD4−/−) mice had impaired HSV-2-specific IFN-γ production and DTH responses and succumbed rapidly to genital HSV-2 challenge. However, protective responses to HSV-2 could be induced in HSV-2-vaccinated CD4−/− mice by treatment with recombinant IFN-γ. Taken together, these results suggest that CD4+ T cells secreting IFN-γ are critical for immune protection against lethal genital HSV-2 re-infection, whereas B cells/natural antibodies have anti-viral and -inflammatory effects in the innate control of a primary infection.

scholarly journals Pharmacological Inhibition of IRE-1 Alpha Activity in Herpes Simplex Virus Type 1 and Type 2-Infected Dendritic Cells Enhances T Cell Activation

2022 ◽  
Vol 12 ◽  
Author(s):  
Eduardo I. Tognarelli ◽  
Angello Retamal-Díaz ◽  
Mónica A. Farías ◽  
Luisa F. Duarte ◽  
Tomás F. Palomino ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are life-long and highly prevalent in the human population. These viruses persist in the host, eliciting either symptomatic or asymptomatic infections that may occur sporadically or in a recurrent manner through viral reactivations. Clinical manifestations due to symptomatic infection may be mild such as orofacial lesions, but may also translate into more severe diseases, such as ocular infections that may lead to blindness and life-threatening encephalitis. A key feature of herpes simplex viruses (HSVs) is that they have evolved molecular determinants that hamper numerous components of the host’s antiviral innate and adaptive immune system. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), by inhibiting their T cell-activating capacity and eliciting their apoptosis after infection. Previously, we reported that HSV-2 activates the splicing of the mRNA of XBP1, which is related to the activity of the unfolded protein response (UPR) factor Inositol-Requiring Enzyme 1 alpha (IRE-1α). Here, we sought to evaluate if the activation of the IRE-1α pathway in DCs upon HSV infection may be related to impaired DC function after infection with HSV-1 or HSV-2. Interestingly, the pharmacological inhibition of the endonuclease activity of IRE-1α in HSV-1- and HSV-2-infected DCs significantly reduced apoptosis in these cells and enhanced their capacity to migrate to lymph nodes and activate virus-specific CD4+ and CD8+ T cells. These findings suggest that the activation of the IRE-1α-dependent UPR pathway in HSV-infected DCs may play a significant role in the negative effects that these viruses exert over these cells and that the modulation of this signaling pathway may be relevant for enhancing the function of DCs upon infection with HSVs.

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