CD8+ T cells control corneal disease following ocular infection with herpes simplex virus type 1

Abstract

The role that T cell subsets play in herpetic stromal keratitis (HSK) has been the subject of intense research efforts. While most studies implicate CD4 + T cells as the principal cell type mediating primary corneal disease, recent reports using knockout mice have suggested that both CD4 + and CD8 + T cell subsets may play integral roles in modulating the disease. Furthermore, recent studies suggest that CD8 + T cells are directly involved in maintaining virus latency in infected trigeminal ganglia. This work has addressed these discrepancies by infecting the corneas of mice lacking CD4 + and CD8 + T cells with herpes simplex virus type 1 (HSV-1) and monitoring both corneal disease and latent infection of trigeminal ganglia. Results indicated that mice lacking CD8 + T cells had more severe corneal disease than either BALB/c or B6 parental strains. In contrast, mice lacking CD4 + T cells had a milder disease than parental strains. When mice were evaluated for persistence of infectious virus, only transient differences were observed in periocular tissue and corneas. No significant differences were found in persistence of virus in trigeminal ganglia or virus reactivation from explanted ganglia. These data support the following conclusions. CD4 + T cells are not required for resistance to infection with HSV-1 and probably mediate HSK. Mice lacking CD8 + T cells do not display differences in viral loads or reactivation and thus CD8 + T cells are not absolutely required to maintain latency. Finally, CD8 + T cells probably play a protective role by regulating the immunopathological response that mediates HSK. INTRODUCTIONHerpetic stromal keratitis (HSK) is a potentially blinding corneal inflammation that accompanies herpes simplex virus (HSV) infection of the eye. The disease course in HSK begins with a primary infection by HSV followed by a period during which the virus enters latency in sensory and autonomic ganglia. Many studies have shown that clinical disease is the result of a cocktail of inflammatory cells consisting of polymorphonuclear leukocytes, macrophages and T cells (both CD4 + and CD8 + ) that are recruited to the corneas of patients with HSK (Maertzdorf et al., 2003;Pepose et al., 1996;Thomas & Rouse, 1997;Youinou et al., 1985Youinou et al., , 1986.Corneas removed from patients requiring corneal transplants due to HSK contain both CD4 + and CD8 + T cells that are specific for HSV-encoded antigens (Koelle et al., 2000). In most models of HSK, T cells are critical to the development of corneal lesions, as athymic nude mice do not display signs of HSK (Metcalf et al., 1979) unless adoptive transfer of T cells is performed (Russell et al., 1984). While most investigators believe that the CD4 + subset of T cells mediates this disease, some reports implicate CD8 + T cells as having a major role in primary HSV keratitis (Akova et al., 1993;Doymaz & Rouse, 1992;Hendricks & Tumpey, 1990;Niemialtowski & Rouse, 1992). Furthermore, when most corneas are immunohistochemically stained for T cell subsets, the predomin...

Phenotypic and Functional Characterization of Herpes Simplex Virus Glycoprotein B Epitope-Specific Effector and Memory CD8+T Cells from Symptomatic and Asymptomatic Individuals with Ocular Herpes

“…In animal models of herpes infection and disease, HSV-specific CD8 ϩ T cells play a critical role in aborting attempts of virus reactivation from latency and in clearing herpetic disease (3,5,(13)(14)(15)(16). However, herpetic corneal disease is also associated with HSV-specific CD8 ϩ T cell responses (17,18).…”

CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection

“…Although PMNs are one of the initial cells that traffic to the cornea [3], CD4 + and CD8 + T lymphocytes are thought to be key components in the development of lesions associated with herpetic stromal keratitis [4][5][6][7]. Th2 cytokines exacerbate HSV-1 infection whereas Th1 cytokines are principally produced by those cells infiltrating the infected tissue and contribute towards resistance to virus replication and spread [8][9][10].…”

“…Both CXCL9 and CXCL10 are expressed or upregulated in the cornea and TG in response to corneal infection with HSV-1 [12]. Since T cells are recruited to the inflammatory site during acute ocular HSV-1 infection [4][5][6][7] and CXCL9 and CXCL10 are associated with the recruitment of activated T cells during inflammatory processes [19][20][21][22][23][24], questions remain as to the temporal nature of expression, redundancy in recruitment of T cells, and the impact of expression on the production of other cytokines and chemokines in the inflamed tissue following infection. To address these questions, mice deficient in CXCL9 (CXCL9−/−) or CXCL10 (CXCL10−/−) were compared to wild type (WT) controls for resistance to infection and the local host immune response following placement of the virus onto the cornea.…”

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…In animal models of herpesvirus infection and disease, HSV-specific CD8 ϩ T cells play a critical role in aborting attempts of virus reactivation from latency and in clearing herpetic disease (2,4,14,(23)(24)(25). However, herpetic corneal disease is also associated with HSV-specific CD8 ϩ T-cell responses (26,27).…”