PMID- 28490594 OWN - NLM STAT- MEDLINE DCOM- 20170726 LR - 20181113 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 91 IP - 15 DP - 2017 Aug 1 TI - Dok-1 and Dok-2 Are Required To Maintain Herpes Simplex Virus 1-Specific CD8(+) T Cells in a Murine Model of Ocular Infection. LID - 10.1128/JVI.02297-16 [doi] LID - e02297-16 AB - 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. Here, 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 wild-type (WT) and Dok-1 and Dok-2 double-knockout (DKO) mice, and the percentages of infiltrating leukocytes were similar in DKO and WT corneas 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 spleens 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. CI - Copyright (c) 2017 American Society for Microbiology. FAU - Lahmidi, Soumia AU - Lahmidi S AD - INRS-Institut Armand-Frappier, Laval, Quebec, Canada. FAU - Yousefi, Mitra AU - Yousefi M AD - INRS-Institut Armand-Frappier, Laval, Quebec, Canada. FAU - Dridi, Slimane AU - Dridi S AD - INRS-Institut Armand-Frappier, Laval, Quebec, Canada. FAU - Duplay, Pascale AU - Duplay P AD - INRS-Institut Armand-Frappier, Laval, Quebec, Canada pascale.duplay@iaf.inrs.ca angela.pearson@iaf.inrs.ca. FAU - Pearson, Angela AU - Pearson A AD - INRS-Institut Armand-Frappier, Laval, Quebec, Canada pascale.duplay@iaf.inrs.ca angela.pearson@iaf.inrs.ca. LA - eng GR - MOP-82924/CIHR/Canada GR - MOP-74445/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170712 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (DNA-Binding Proteins) RN - 0 (Dok1 protein, mouse) RN - 0 (Dok2 protein, mouse) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (Immunodominant Epitopes) RN - 0 (Phosphoproteins) RN - 0 (RNA-Binding Proteins) RN - 0 (Viral Envelope Proteins) RN - 0 (glycoprotein B, human herpesvirus 1) SB - IM MH - Adaptor Proteins, Signal Transducing/deficiency/*metabolism MH - Animals MH - CD8-Positive T-Lymphocytes/*immunology MH - DNA-Binding Proteins/deficiency/*metabolism MH - Disease Models, Animal MH - Epitopes, T-Lymphocyte/immunology MH - Herpesvirus 1, Human/*immunology MH - Immunodominant Epitopes/immunology MH - Keratitis, Herpetic/*immunology MH - Lymph Nodes/immunology MH - Mice MH - Mice, Knockout MH - Phosphoproteins/deficiency/*metabolism MH - RNA-Binding Proteins/*metabolism MH - Spleen/immunology MH - Trigeminal Ganglion/immunology/virology MH - Viral Envelope Proteins/immunology PMC - PMC5512252 OTO - NOTNLM OT - CD8+ T cell OT - Dok proteins OT - T cell immunity OT - herpes simplex virus OT - herpesviruses OT - viral pathogenesis EDAT- 2017/05/12 06:00 MHDA- 2017/07/27 06:00 PMCR- 2018/01/12 CRDT- 2017/05/12 06:00 PHST- 2016/11/30 00:00 [received] PHST- 2017/05/02 00:00 [accepted] PHST- 2017/05/12 06:00 [pubmed] PHST- 2017/07/27 06:00 [medline] PHST- 2017/05/12 06:00 [entrez] PHST- 2018/01/12 00:00 [pmc-release] AID - JVI.02297-16 [pii] AID - 02297-16 [pii] AID - 10.1128/JVI.02297-16 [doi] PST - epublish SO - J Virol. 2017 Jul 12;91(15):e02297-16. doi: 10.1128/JVI.02297-16. Print 2017 Aug 1.