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

Abstract

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

Tissue-resident lymphocytes: from adaptive to innate immunity

“…64 In addition to cytokines, chemokines are also important in the trafficking and localization of T RM cells. For example, the chemokine receptors CXCR6 and CCR10 are required for optimal formation of a T RM population in the skin; lack of either CXCL10 or CXCR3 compromises the mobilization of T RM cells within latently infected trigeminal ganglia and results in the absence of signals required for differentiation 15,65,66 ; CXCR3 is also critical for T cell accumulation in uninfected salivary glands, 67 and CXCL17 is required for the mobilization of T RM cells in the vaginal mucosa (VM). 68 Differentiation of recirculating T EM cells depends on prolonged cognate antigen stimulation.…”

“…68 Significant increases in both the number and function of HSV-specific CXCR3 + T RM cells have been detected in the trigeminal ganglia of mice following UV-B-induced HSV-1 reactivation, which protects the host from recurrent HSV infection, and a lack of T RM is again associated with recurrent ocular HSV infection. 65 In addition, accumulation of T RM cells in the skin provides enhanced control against viral infection with HSV-1. 11,62,82 T RM cells generated by the "prime and pull" protocol may reduce the spread of infectious HSV-2 into the sensory neurons and prevent development of clinical disease.…”

Resolution of herpes simplex virus reactivation in vivo results in neuronal destruction

“…Of these, the CD4 + and CD8 + T cells have been shown to be important for resolution of the acute infection [44] and CD8 + T cells directed against an epitope on glycoprotein B are hypothesized to maintain the latent state [76] and there is evidence that this is dependent on MHC class I expression [77]. Further, CXCR3 + CD8 + T cells have been shown to increase in the TG and the epithelial surface following a reactivation stimulus and this correlated with a decrease in viral shedding at the surface, noting that outcomes in the TG were not examined [78]. It has also been proposed that regulatory T cells function to suppress CD8 + T cells and facilitate HSV reactivation [79].…”

Prime-and-Trap Malaria Vaccination To Generate Protective CD8+ Liver-Resident Memory T Cells

“…Prime-and-pull was developed to establish local tissue Trm cells at target sites by parenterally vaccinating to elicit systemic T cell responses (prime) and then to recruit activated T cells to specific tissues with a topical chemokine (66) or with nonspecific inflammation (67) (pull), where such T cells could become Trm cells and mediate protection. Methods have been reported for the liver (19), urogenital tract (66,68,69), and lungs (70,71). The recent malaria prime-and-trap report showed that TCR transgenic cells adoptively transferred into naive recipient mice could be primed with peptide-pulsed DCs and then trapped with a liver-specific, Ag-expressing recombinant adeno-associated virus (19).…”