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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, Soumia; Yousefi, Mitra; Dridi, Slimane; Duplay, Pascale; Pearson, Angela (2017). Dok-1 and Dok-2 are required to maintain herpes simplex virus 1-specific CD8+ T cells in a murine model of ocular infection Journal of Virology . p. 1-16. DOI: 10.1128/JVI.02297-16. (Sous Presse)

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Résumé

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+ 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. Herein, 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 WT and in Dok-1 and Dok-2 double knock-out (DKO) mice, and the percentage of infiltrating leukocytes was similar in DKO and WT cornea and trigeminal ganglia (TG). DKO mice exhibited a diminished CD8+ 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+ T cells almost completely disappeared in the spleen of DKO mice during latency, and the reduction of CD8+ effector memory T (Tem) cells was more severe than that of CD8+ central memory T (Tcm) cells. The percentage of gB-specific CD8+ 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+ 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+ 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+ T cell response against HSV-1 during latency-especially CD8+ 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.

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Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 27 juin 2017 01:30
Dernière modification: 27 juin 2017 01:32
URI: http://espace.inrs.ca/id/eprint/5387

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