PMID- 28468883 OWN - NLM STAT- MEDLINE DCOM- 20170718 LR - 20220318 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 91 IP - 14 DP - 2017 Jul 15 TI - 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. LID - 10.1128/JVI.00278-17 [doi] LID - e00278-17 AB - Herpes simplex virus 1 (HSV-1) establishes latency within the sensory neurons of the trigeminal ganglia (TG). HSV-specific memory CD8(+) 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(+) 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(+) 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(+) CD8(+) T cells was detected in TG and corneas of protected C57BL/6 (B6) mice, but not in TG and corneas of nonprotected CXCL10(-/-) or CXCR3(-/-) 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(-/-) mice, using the neurotropic adeno-associated virus type 8 (AAV8) vector, boosted the number and function of effector memory CD8(+) T cells (T(EM)) and tissue-resident memory CD8(+) T cells (T(RM)), but not of central memory CD8(+) T cells (T(CM)), locally within TG, and improved protection against recurrent herpesvirus infection and disease in CXCL10(-/-) deficient mice. These findings demonstrate that the CXCL10/CXCR3 chemokine pathway is critical in shaping CD8(+) 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(+) T cell responses to recurrent ocular herpesvirus infection and disease. Using a well-established 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(+) T(EM) and CD8(+) 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 CXCL10 in trigeminal ganglia of latently infected CXCL10-deficient mice significantly restored the number of local antiviral CD8(+) T(EM) and CD8(+) T(RM) cells associated with protection against recurrent ocular herpes. Based on these findings, a novel "prime/pull" therapeutic ocular herpes vaccine strategy is proposed and discussed. CI - Copyright (c) 2017 American Society for Microbiology. FAU - Srivastava, Ruchi AU - Srivastava R AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Khan, Arif A AU - Khan AA AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Chilukuri, Sravya AU - Chilukuri S AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Syed, Sabrina A AU - Syed SA AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Tran, Tien T AU - Tran TT AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Furness, Julie AU - Furness J AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Bahraoui, Elmostafa AU - Bahraoui E AD - INSERM, U1043, and CNRS, U5282, Toulouse, France. AD - Universite Paul Sabatier Toulouse, Toulouse, France. FAU - BenMohamed, Lbachir AU - BenMohamed L AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA Lbenmoha@uci.edu. AD - Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California, USA. AD - Institute for Immunology, University of California Irvine, School of Medicine, Irvine, California, USA. LA - eng GR - R01 EY026103/EY/NEI NIH HHS/United States GR - R01 EY019896/EY/NEI NIH HHS/United States GR - R21 AI110902/AI/NIAID NIH HHS/United States GR - UL1 TR001414/TR/NCATS NIH HHS/United States GR - R01 EY024618/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170626 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Chemokine CXCL10) RN - 0 (Cxcl10 protein, mouse) RN - 0 (Cxcr3 protein, mouse) RN - 0 (Receptors, CXCR3) SB - IM MH - Animals MH - CD8-Positive T-Lymphocytes/*immunology MH - Chemokine CXCL10/deficiency/*metabolism MH - Cornea/immunology/virology MH - Disease Models, Animal MH - Herpes Simplex/*immunology/prevention & control MH - *Immunologic Memory MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Receptors, CXCR3/deficiency/*metabolism MH - Recurrence MH - Simplexvirus/*immunology MH - Trigeminal Ganglion/immunology/virology PMC - PMC5487556 OTO - NOTNLM OT - CD8 OT - CD8+ T cells OT - CXCL10 OT - CXCR3 OT - chemokine receptors OT - chemokines OT - herpes simplex virus OT - immunization OT - trigeminal ganglia EDAT- 2017/05/05 06:00 MHDA- 2017/07/19 06:00 PMCR- 2017/12/26 CRDT- 2017/05/05 06:00 PHST- 2017/02/16 00:00 [received] PHST- 2017/04/25 00:00 [accepted] PHST- 2017/05/05 06:00 [pubmed] PHST- 2017/07/19 06:00 [medline] PHST- 2017/05/05 06:00 [entrez] PHST- 2017/12/26 00:00 [pmc-release] AID - JVI.00278-17 [pii] AID - 00278-17 [pii] AID - 10.1128/JVI.00278-17 [doi] PST - epublish SO - J Virol. 2017 Jun 26;91(14):e00278-17. doi: 10.1128/JVI.00278-17. Print 2017 Jul 15.