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Lbachir BenMohamed, Anthony B. Nesburn, Ruchi Srivastava; The CXCL10/CXCR3 Chemokine Pathway is Required for the Generation and Protective Function of Tissue-Resident Memory CD103+CD8+ TRM Cells Against Recurrent Ocular Herpes. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3621.
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Tissue-resident memory (TRM) CD8+ T cells are generated in non-lymphoid peripheral tissues and provide host protection against viral infections. However, the mechanisms that control the generation, accumulation and protective function of CD8+ TRM cells within the target peripheral infected tissues remain to be fully elucidated.
Here we used a well-establish murine model of recurrent ocular herpes simplex virus type 1 (HSV-1) infection to determine whether and how localized peripheral tissue-specific viral infection generates functional CD8+ TRM cells. Virus reactivation was induced by UV-B light in trigeminal ganglia (TG) of HSV-1 latently infected B6 mice, and virus shedding in tears triggered recurrent corneal herpetic disease.
This led to a significant increase in both the number and effector function of local CXCR3+CD103+CD8+ TRM cells, assessed by tetramer frequency, antiviral IFN-g, TNF-a and CD107a/b cytotoxic degranulation assays. The increase in polyfunctional TG-resident CXCR3+CD103+CD8+ TRM cells was associated with a significant reduction of virus shedding and prevention of recurrent corneal herpetic disease. In contrast, UV-B induced virus reactivation in mice deficient for CXCL10, or for CXCR3, led to increased virus shedding and severe recurrent corneal herpetic disease associated with accumulation of dysfunctional/exhausted PD-1+VISTA+TIGIT+CD8+ TRM cells in TG and cornea (COR). Furthermore, topical ocular application of a neurotropic AAV8 vector expressing CXCL10, but not CXCL9, chemokine specifically in TG and COR rescued the number and promoted the protective function of CD103+CD8+ TRM cells in CXCL10−/− deficient mice.
These findings demonstrate a crucial role of CXCL10/CXCR3 pathway in shaping protective CD103+CD8+ TRM cell immunity against recurrent ocular herpes.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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