Presence of HSV‐1 Immediate Early Genes and Clonally Expanded T‐cells with a Memory Effector Phenotype in Human Trigeminal Ganglia

Ganglia of monkeys with reactivated simian varicella virus (SVV) contained more CD8 than CD4 T cells around neurons. The abundance of CD8 T cells was greater less than 2 months after reactivation than that at later times and correlated with that of CXCL10 RNA but not with those of SVV protein or open reading frame 61 (ORF61) antisense RNA. CXCL10 RNA colocalized with T-cell clusters. After SVV reactivation, transient T-cell infiltration, possibly mediated by CXCL10, parallels varicella zoster virus (VZV) reactivation in humans. Varicella zoster virus (VZV) causes varicella (chickenpox) and becomes latent in ganglia, producing zoster (shingles) upon reactivation. Because VZV infects only humans, studies of virus latency and reactivation have been restricted to autopsy tissues. Analyses of ganglia obtained after death from individuals with recent zoster revealed lymphocytic infiltration (1, 2), possibly mediated by antigenic stimuli or chemokines, including CXCL10 (3). VZV-specific T cells have not been identified in human ganglia latently infected with VZV (4, 5). Simian varicella virus (SVV) infection in monkeys closely resembles VZV infection in humans (6). Earlier, we demonstrated reactivation of latent SVV in immunosuppressed monkeys (7). Herein, we extended those studies by examining ganglia containing reactivated SVV for infiltrating T cells. Four cynomolgus macaques (GP02, -04, -06, and -07) were naturally infected with SVV (7). Ten to 14 days later, all monkeys developed varicella ( Fig. 1). At 4 months postinfection, monkeys were immunosuppressed with tacrolimus, resulting in a 34% reduction in mean white blood cell counts at 6 weeks posttreatment (7). Monkeys GP02, -06, and -07 developed zoster at 23, 3, and 10 days, respectively, after starting tacrolimus. Monkeys were euthanized at monthly intervals post-tacrolimus treatment (Fig. 1). Detection of SVV glycoproteins in lungs and multiple ganglia in monkey GP04, which did not develop skin rash, confirmed subclinical reactivation (7).Immunohistochemical analysis of consecutive ganglion tissue sections from these monkeys and from an uninfected control monkey (CTRL) for CD3, CD4 and CD8 expression showed that SVV reactivation was associated with T-cell infiltration, mostly CD8 T cells, in ganglia along the entire neuraxis (Fig. 2). T cells were dispersed throughout ganglia. T-cell clusters, of both CD4 and CD8 T cells, were occasionally detected adjacent to neurons ( Fig. 2A). Rare granzyme B ϩ (grB) cells, not restricted to T-cell clusters, were observed in ganglia from all monkeys ( Fig. 2A), suggesting that ganglion-infiltrating T cells did not encounter their cognate antigen (8). Ganglion-infiltrating CD8 T cells in zoster patients are also predominantly grB negative (9).We analyzed 11 to 19 ganglia from each monkey to determine the number of T cells per neuron. The number of ganglionic neurons counted in sections from each anatomical level of the neuraxis ranged from 657 to 3,991 (Table 1). Ganglia obtained from monkey GP02, euthanized at 4 days post-...

Section: Fig 2 Increased Number Of Ganglion-infiltrating T Cells and supporting

confidence: 75%

T-Cell Infiltration Correlates with CXCL10 Expression in Ganglia of Cynomolgus Macaques with Reactivated Simian Varicella Virus

Ouwendijk

Abendroth

Traina‐Dorge

et al. 2013

“…We next determined the role of the CXCR3 signaling pathway in the mobilization and/or accumulation of the three major CD8 ϩ T cell subpopulations (i.e., CD8 ϩ T EM cells, CD8 ϩ T CM cells, and CD8 ϩ T RM cells) in the cornea and TG, in addition to their relative contribution in the observed protection against virus shedding and recurrent herpetic disease. Of the three T cell-attracting ligands of CXCR3 (i.e., CXCL9, CXCL10, and CXCL11), CXCL10 is the only chemokine that is predominantly expressed in human TG (19,35). We therefore A group of 20 sex-and age-matched CXCL10-deficient mice (CXCL10 Ϫ/Ϫ ) and 20 WT B6 control littermates were infected ocularly on day 0 with 2 ϫ 10 5 PFU of HSV-1 without corneal scarification as described in Materials and Methods.…”

Section: Resultsmentioning

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

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

“…ϩ -T-cell infiltrate and the presence of inflammatory cytokines, suggesting that the presence of activated, effector memory cells within the PNS is important for maintaining HSV-1 latency in the natural human host (10,42).…”

mentioning

confidence: 99%

CD4⁺T Cells Are Required for the Priming of CD8⁺T Cells following Infection with Herpes Simplex Virus Type 1

Rajasagi

Kassim

Kollias

et al. 2009

The role of CD4؉ helper T cells in modulating the acquired immune response to herpes simplex virus type 1 (HSV-1) remains ill defined; in particular, it is unclear whether CD4 ؉ T cells are needed for the generation of the protective HSV-1-specific CD8؉ -T-cell response. This study examined the contribution of CD4 ؉ T cells in the generation of the primary CD8؉ -T-cell responses following acute infection with HSV-1. The results demonstrate that the CD8 ؉ -T-cell response generated in the draining lymph nodes of CD4 ؉ -T-cell-depleted C57BL/6 mice and B6-MHC-II ؊/؊ mice is quantitatively and qualitatively distinct from the CD8 ؉ T cells generated in normal C57BL/6 mice. Phenotypic analyses show that virus-specific CD8 ؉ T cells express comparable levels of the activation marker CD44 in mice lacking CD4 ؉ T cells and normal mice. In contrast, CD8؉ T cells generated in the absence of CD4 ؉ T cells express the interleukin 2 receptor ␣-chain (CD25) at lower levels. Importantly, the CD8 ؉ T cells in the CD4؉ -T-cell-deficient environment are functionally active with respect to the expression of cytolytic activity in vivo but exhibit a diminished capacity to produce gamma interferon and tumor necrosis factor alpha. Furthermore, the primary expansion of HSV-1-specific CD8 ؉ T cells is diminished in the absence of CD4؉ -T-cell help. These results suggest that CD4 ؉ -T-cell help is essential for the generation of fully functional CD8 ؉ T cells during the primary response to HSV-1 infection.