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

Thapa, Manoj; Carr, Daniel J.J.

doi:10.1128/jvi.00854-09

Cited by 51 publications

(62 citation statements)

References 63 publications

(67 reference statements)

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“…Cxcr3 genetic deficiency increases susceptibility to genital herpes simplex-2 virus (HSV-2) (Thapa and Carr, 2009) and intracerebral dengue virus (Ip and Liao, 2010). Interestingly, protection in each of these models is mediated independently of CXCR3-dependent leukocyte recruitment.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

et al. 2015

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SUMMARY CD8+ T cells play a critical role limiting peripheral virus replication, yet how they locate virus-infected cells within tissues is unknown. Here, we have examined the environmental signals that CD8+ T cells use to localize and eliminate virus-infected skin cells. Epicutaneous vaccinia virus (VV) infection, mimicking human smallpox vaccination, greatly increased expression of the CXCR3 chemokine receptor ligands CXCL9 and -10 in VV-infected skin. Despite normal T cell numbers in the skin, Cxcr3−/− mice exhibited dramatically impaired CD8+ T cell-dependent virus clearance. Intravital microscopy revealed that Cxcr3−/− T cells were markedly deficient in locating, engaging, and killing virus-infected cells. Further, transfer of wild-type CD8+ T cells restored viral clearance in Cxcr3−/−animals. These findings demonstrate a function for CXCR3 in enhancing the ability of tissue-localized CD8+ T cells to locate virus-infected cells and thereby exert anti-viral effector functions.

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Section: Discussionmentioning

confidence: 99%

CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

et al. 2015

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“…CXCL10 deficiency was associated with a reduction in the mobilization of HSV-specific CD8 ϩ T cells into the brain as a result of dysregulation of CXCR3 signaling (31). CXCR3 Ϫ/Ϫ deficient mice are also reported to be susceptible to primary genital HSV-2 infection (61)(62)(63)(64). This susceptibility appeared to be associated with reduced cytotoxic function of CD8 ϩ T cells through impairment in expression of T-bet, perforin, and GzmB, as well as a reduction in the recruitment of pDC and impairment in CD80 expression on CD11c ϩ DC (61)(62)(63)(64).…”

Section: Discussionmentioning

confidence: 99%

“…CXCR3 Ϫ/Ϫ deficient mice are also reported to be susceptible to primary genital HSV-2 infection (61)(62)(63)(64). This susceptibility appeared to be associated with reduced cytotoxic function of CD8 ϩ T cells through impairment in expression of T-bet, perforin, and GzmB, as well as a reduction in the recruitment of pDC and impairment in CD80 expression on CD11c ϩ DC (61)(62)(63)(64). It is important to underline that, unlike the above studies that were done using mouse models of acute ocular and genital primary infections, our present studies used a mouse model of induced virus reactivation and recurrent herpes.…”

Section: Discussionmentioning

confidence: 99%

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Srivastava

Khan

Chilukuri

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency within the sensory neurons of the trigeminal ganglia (TG). HSV-specific memory CD8 ϩ T cells play a critical role in preventing HSV-1 reactivation from TG and subsequent virus shedding in tears that trigger recurrent corneal herpetic disease. The CXC chemokine ligand 10 (CXCL10)/CXC chemokine receptor 3 (CXCR3) chemokine pathway promotes T cell immunity to many viral pathogens, but its importance in CD8 ϩ T cell immunity to recurrent herpes has been poorly elucidated. In this study, we determined how the CXCL10/CXCR3 pathway affects TG-and cornea-resident CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease using a well-established murine model in which HSV-1 reactivation was induced from latently infected TG by UV-B light. Following UV-B-induced HSV-1 reactivation, a significant increase in both the number and function of HSV-specific CXCR3 ϩ CD8 ϩ T cells was detected in TG and corneas of protected C57BL/6 (B6) mice, but not in TG and corneas of nonprotected CXCL10 Ϫ/Ϫ or CXCR3 Ϫ/Ϫ deficient mice. This increase was associated with a significant reduction in both virus shedding and recurrent corneal herpetic disease. Furthermore, delivery of exogenous CXCL10 chemokine in TG of CXCL10 Ϫ/Ϫ mice, using the neurotropic adeno-associated virus type 8 (AAV8) vector, boosted the number and function of effector memory CD8 ϩ T cells (T EM ) and tissue-resident memory CD8 ϩ T cells (T RM ), but not of central memory CD8 ϩ T cells (T CM ), locally within TG, and improved protection against recurrent herpesvirus infection and disease in CXCL10 Ϫ/Ϫ deficient mice. These findings demonstrate that the CXCL10/CXCR3 chemokine pathway is critical in shaping CD8 ϩ T cell immunity, locally within latently infected tissues, which protects against recurrent herpesvirus infection and disease.IMPORTANCE We determined how the CXCL10/CXCR3 pathway affects CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease. Using a wellestablished murine model, in which HSV-1 reactivation in latently infected trigeminal ganglia was induced by UV-B light, we demonstrated that lack of either CXCL10 chemokine or its CXCR3 receptor compromised the mobilization of functional CD8 ϩ T EM and CD8 ϩ T RM cells within latently infected trigeminal ganglia following virus reactivation. This lack of T cell mobilization was associated with an increase in recurrent ocular herpesvirus infection and disease. Inversely, augmenting the amount of

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“…33 Thus, T-bet can regulate independently: (1) the effector functions of the AFCs and of memory B cells by influencing the Ig isotype they produce, 23,32 (2) their migratory behavior, 14 (3) and possibly, through regulation of CXCR3, the amplitude 34 or the longevity 33 of antibody responses. This pleiotropic function of T-bet has been also found for CD8, 13,24,35 CD4 effector, 24,27 or regulatory 36 T lymphocytes, NK, 24,37,38 and NKT 36,39 cells. The present study on B cells adds to the list of the many important functions that T-bet helps to coordinate during IFN-␥-mediated inflammatory responses.…”

Section: Ifn-␥/t-bet-dependent Cxcr3 Induction In B Cells 4557mentioning

confidence: 52%

“…11 This CXCR3-dependent pathway is important for the recruitment of lymphocytes at sites of infection and clearance of pathogens. 12,13 For instance, CXCR3 expression by mouse AFCs is critical for their migration to the CNS during viral encephalomyelitis. Thus, CXCR3-dependent migration of AFCs to the site of infection clears the virus from the CNS, although this is not achieved with systemic release of antibody.…”

Section: Introductionmentioning

confidence: 99%

CD8 T cells induce T-bet–dependent migration toward CXCR3 ligands by differentiated B cells produced during responses to alum-protein vaccines

Serre

Cunningham

Coughlan

et al. 2012

Blood

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IntroductionHomeostatic chemokines, including CXCL13, CXCL19/CXCL21, and CXCL12, are essential organizers of lymphoid tissues in steady states. For instance, they govern the compartmentalization between T and B cells. Importantly, they are also involved in the repositioning of these lymphocytes during the different stages of immune responses. The development of protective memory B cells and long-lived AFCs relies in part on changing expression by the responding B cells of the receptors for the chemokines CXCR5, CCR7, and CXCR4, and of the orphan receptor Epstein-Barr virus-induced molecule-2. 1-3 Thus, during the development of T-dependent antibody responses to protein-based antigens, such as alum-precipitated protein vaccines, chemokine-driven movements in lymph nodes (LNs) are sequentially involved in: (1) the cognate interaction of activated B cells with primed CD4 T cells [4][5][6] in the outer T zone, resulting in B-cell proliferation and class-switch recombination (CSR); or (2) the signals that determine whether B blasts differentiate outside follicles into AFCs without going through affinity maturation 1,3 or form germinal center (GC) in follicles. 2 Through CXCR4-and CXCR5-dependent movements, B cells undergo affinity maturation in GC through proliferation, hypermutation of their immunoglobulin (Ig) variable region genes, and selection of high-affinity mutants that emerge as memory B cells or long-lived AFCs. 7,8 The acquisition of CXCR4 by AFC attracts them to CXCL12 produced in bone marrow's long-term survival niches. In these niches, they maintain protective antibody titers over months. 9,10 Alongside the varying expression of CXCR5/CCR7/CXCR4 that modulates B-cell chemotaxis toward homeostatic chemokines, inflammatory conditions can induce IFN-␥-dependent expression of CXCR3 by lymphocytes, including AFCs. This receptor confers responsiveness to CXCL9, CXCL10, and CXCL11, which are produced at high levels in sites of inflammation. 11 This CXCR3-dependent pathway is important for the recruitment of lymphocytes at sites of infection and clearance of pathogens. 12,13 For instance, CXCR3 expression by mouse AFCs is critical for their migration to the CNS during viral encephalomyelitis. Thus, CXCR3-dependent migration of AFCs to the site of infection clears the virus from the CNS, although this is not achieved with systemic release of antibody. 14,15 CXCR3 ϩ AFCs and memory B cells were found at particularly high frequency in peripheral blood of patients with autoimmune diseases mediated by autoantibodies. 16,17 This suggests that selfreactive AFCs may be produced and/or attracted to and sustained in chronic inflammatory niches through a mechanism that involves CXCR3 and its ligands. 18 In mouse models for lupus erythematosus, AFCs are found in inflamed tissues. 19 Knockdown of CXCR3 has shown the importance of this chemokine receptor in the development of the autoimmune disorders, 20 including the production anti-double-stranded DNA IgG1. 21 Despite the importance of CXCR3 induction for antibody producti...

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

Abstract: CXCR3 is a G-protein-coupled receptor preferentially expressed by activated T cells, NK cells

Cited by 51 publications

References 63 publications

CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

CD8 T cells induce T-bet–dependent migration toward CXCR3 ligands by differentiated B cells produced during responses to alum-protein vaccines

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

Abstract: CXCR3 is a G-protein-coupled receptor preferentially expressed by activated T cells, NK cells

Cited by 51 publications

References 63 publications

CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

CD8 T cells induce T-bet–dependent migration toward CXCR3 ligands by differentiated B cells produced during responses to alum-protein vaccines

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

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease