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Lbachir BenMohamed, Arif Khan, Ruchi Srivastava, Thanh T Pham, Patricia P Lopes, Bertrand Wechsler, Anthony B Nesburn; Differential Role of HSV-Specific Central vs. Effector Memory CD8+ T Cells in Ocular Herpes Disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4061.
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Most HSV-1 infected individuals are asymptomatic (ASYMP). They do not experience any recurrent ocular herpetic disease even though spontaneously reactivated virus is surreptitiously shed in their tears. In contrast, a small proportion of HSV-seropositive individuals are symptomatic (SYMP) and experience persistant recurrences of ocular herpetic disease, often requiring continuous antiviral therapy (i.e., acyclovir derivatives) or corneal transplantation. Understanding the immune mechanisms by which ASYMP individuals control herpetic disease is crucial for the design of future therapeutic vaccines.
In this study we used ten tetramers specific to HLA-A*0201-restricted gB epitopes together with KLRG-1 and CD127 markers to determine the nature and frequency of HSV-specific memory CD8+ T-cell subsets present in the peripheral blood of HLA-A*0201 positive and HSV-seropositive asymptomatic vs. symptomatic individuals. The function of gB-specific effector (TEM) and central memory (TCM) CD8+ T-cells was assessed by a combination of IFN-γ-ELISpot and CD107a/b cytotoxic degranulation assay.
A significantly higher percentage of Short Lived Effector Cells (SLECs, KLRG-1+CD127-) was found in asymptomatic compared to symptomatic individuals. In contrast, no difference in Memory Precursors Effector Cells (MPECs, KLRG-1-CD127+) was detected between the two groups. Asymptomatic individuals showed significantly higher percentage of gB-specific TEM CD8+ T-cells while symptomatic individuals showed more gB-specific TCM CD8+ T-cells. Asymptomatic individuals had a significantly higher proportion of HSV-gB-specific CD8+ T-cells expressing CD107a/b degranulation marker and produced more effector cytokines IL-2, IFN-γ, and TNF-α, compared to symptomatic individuals. Moreover, immunization of a novel herpes susceptible HLA-A*02:01 transgenic mouse model with TEM, but not TCM gB epitopes, induced strong CD8+ T-cell-dependent protective immunity against ocular herpes infection and disease.
Altogether, our results indicate that HSV-specific SLECs and TEM CD8+ T-cells are associated with protection against herpes in both human and HLA transgenic mice. These findings should guide the development of a safe and effective CD8+ T-cell-based herpes vaccine.
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