Elucidating the protective and pathologic T cell species in the virus-induced corneal immunoinflammatory condition herpetic stromal keratitis

Dok-1 and Dok-2 negatively regulate responses downstream of several immune receptors in lymphoid and myeloid cells. Recent evidence showed that Dok proteins are essential in the formation of memory CD8 ϩ T cells to an exogenous epitope expressed by vaccinia virus; however, the importance of Dok-1 and Dok-2 in the control of viral infection is unknown. Here, we investigated the role of Dok proteins in modulating the immune response against herpes simplex virus 1 (HSV-1) in a mouse model of ocular infection. During acute infection, viral titers in the eye were similar in wild-type (WT) and Dok-1 and Dok-2 double-knockout (DKO) mice, and the percentages of infiltrating leukocytes were similar in DKO and WT corneas and trigeminal ganglia (TG). DKO mice exhibited a diminished CD8 ϩ T cell response to the immunodominant HSV-1 glycoprotein B (gB) epitope in the spleen and draining lymph nodes compared to WT mice during acute infection. Remarkably, gB-specific CD8 ϩ T cells almost completely disappeared in the spleens of DKO mice during latency, and the reduction of CD8 ϩ effector memory T (Tem) cells was more severe than that of CD8 ϩ central memory T (Tcm) cells. The percentage of gB-specific CD8 ϩ T cells in TG during latency was also dramatically reduced in DKO mice; however, they were phenotypically similar to those from WT mice. In ex vivo assays, reactivation was detected earlier in TG cultures from infected DKO versus WT mice. Thus, Dok-1 and Dok-2 promote survival of gB-specific CD8 ϩ T cells in TG latently infected with HSV-1.IMPORTANCE HSV-1 establishes lifelong latency in sensory neurons of trigeminal ganglia (TG). In humans, HSV-1 is able to sporadically reactivate from latently infected neurons and establish a lytic infection at a site to which the neurons project. Most herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. CD8 ϩ T cells are thought to play an important role in controlling recurrent infections. In this study, we examined the involvement of Dok-1 and Dok-2 signaling proteins in the control of HSV-1 infection. We provide evidence that Dok proteins are required to maintain a CD8 ϩ T cell response against HSV-1 during latency-especially CD8 ϩ Tem cells-and that they negatively affect HSV-1 reactivation from latency. Elucidating Dok-mediated mechanisms involved in the control of HSV-1 reactivation from latency might contribute to the development of therapeutic strategies to prevent recurrent HSV-1-induced pathology.KEYWORDS CD8 ϩ T cell, T cell immunity, Dok proteins, herpes simplex virus, herpesviruses, viral pathogenesis F ollowing experimental corneal infection of C57BL/6 (B6) mice, herpes simplex virus 1 (HSV-1) replicates in epithelial cells and then spreads to the trigeminal ganglia (TG) via nerve termini, where it replicates but then ultimately establishes latency in neurons (1). In humans, reactivation of HSV-1 can lead to recurrent lesions on labial

Section: Hsv-1-induced Clinical Signs Are Not Mediated By Dok Proteinsmentioning

confidence: 79%

Dok-1 and Dok-2 Are Required To Maintain Herpes Simplex Virus 1-Specific CD8⁺T Cells in a Murine Model of Ocular Infection

Lahmidi

Yousefi

Dridi

et al. 2017

“…Work from our laboratory and others has shown that the CD8 ϩ T cells are critical for protection against recurrent ocular herpesvirus infection and disease (23,24,39). However, the relative contribution of each of the CD8 ϩ T cell subpopulations in protection against recurrent herpes has not been reported.…”

Section: Discussionmentioning

confidence: 97%

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

“…In animal models of herpes infection and disease, HSV-specific CD8 ϩ T cells play a critical role in aborting attempts of virus reactivation from latency and in clearing herpetic disease (3,5,(13)(14)(15)(16). However, herpetic corneal disease is also associated with HSV-specific CD8 ϩ T cell responses (17,18).…”

Section: Importancementioning

confidence: 99%

Phenotypic and Functional Characterization of Herpes Simplex Virus Glycoprotein B Epitope-Specific Effector and Memory CD8⁺T Cells from Symptomatic and Asymptomatic Individuals with Ocular Herpes

Khan

Srivastava

Spencer

et al. 2015

Herpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8؉ T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8؉ T cells play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8 O ver a billion individuals worldwide carry herpes simplex virus 1 (HSV-1), which causes a wide range of mild to life-threatening diseases (1-3). Although the virus reactivates from latency and is shed multiple times each year in body fluids (i.e., tears, saliva, and nasal and vaginal secretions), most reactivations are subclinical due to an efficient immune-mediated containment of the infection and disease (4-7). Thus, most infected individuals are asymptomatic (ASYMP) and do not present any apparent recurrent herpetic disease (e.g., cold sores, genital, or ocular herpetic disease). However, a small proportion of individuals experience endless recurrences of herpetic disease, usually multiple times a year, often necessitating continuous antiviral therapy (i.e., with acyclovir and derivatives) (8,9). In those symptomatic (SYMP) individuals, HSV-1 frequently reactivates from latency, reinfects the eyes, and may trigger recurrent and severe corneal herpetic disease, a leading cause of infectious corneal blindness in