Restricted T Cell Receptor β‐Chain Variable Region Protein Use by Cornea‐Derived CD4⁺and CD8⁺Herpes Simplex Virus–Specific T Cells in Patients with Herpetic Stromal Keratitis

Abstract

Herpetic stromal keratitis (HSK) is a T helper type 1 cell-mediated inflammatory disease triggered by herpes simplex virus (HSV) infection of the cornea. In contrast to animal models of HSK, little is known about the role of T cells in human HSK. The phenotypes and repertoires of HSV-specific T cells recovered from the corneas of 12 patients with HSK were determined by flow cytometry. Cornea-derived T cell lines (TCLs) from 10 of the 12 patients contained high numbers of HSV-specific T cells. HSV reactivity was HSV type common and involved relatively more CD8(+) than CD4(+) T cells. The majority of the TCLs showed restricted T cell receptor beta-chain variable region protein (TCRBV) use. T cells expressing 1 or 2 TCRBVs dominated the HSV-1 reactivity in 3 of 5 TCLs analyzed. The data demonstrate that both CD4(+) and CD8(+) T cells may be involved in the HSV-specific T cell response in the corneas of patients with HSK and suggest that restricted TCRBV use by cornea-residing HSV-specific T cells occurs.

Epitope mapping of HSV-1 glycoprotein K (gK) reveals a T cell epitope located within the signal domain of gK

“…In this regard, it has been shown that 4-1BB, which has preferential effects on the survival or expansion of CD8 + T cells, is required for the development of herpes stromal keratitis (HSK) (Koelle et al, 1994;Seo et al, 2003;Verjans et al, 1998). It also has been shown that corneal bottoms isolated from HSK patients had higher numbers of HSV-reactive CD8 + T cells than HSV-reactive CD4 + T cells (Maertzdorf et al, 2003).…”

Human herpes simplex virus keratitis: the pathogenesis revisited

“…74, 161 Although the nature of the antigens recognized by the cornea infiltrating T-cells are still unknown, parts of the cascade of inflammatory responses are elucidated by studies in 'mice and man'. 134,175,146,155,156,157,158 Development of new therapeutic strategies targeting specific HSKassociated cytokines/chemokines will be the challenge for the future to treat this sight-threatning disease more effectively. …”

“…156 Intra-corneal TCL obtained from HSK patients contain high numbers of HSV-specific T cells. 158 Both CD4 + and CD8 + T cells are potentially involved in the intra-corneal HSV-specific T cell response. These data oppose results from studies performed in the experimental HSK mouse model in which corneal infiltrating T cells are predominantly of the CD4 + subset.…”

“…Furthermore, the majority of the human intra-corneal TCL showed a restricted usage of T cell receptor Vb domains. 158 Antiviral treatment in ISK is both directed at the presumed presence of the virus and at prevention of severe reactivation of infection during steroid therapy. Topical antivirals should be used in a therapeutic dose.…”

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

“…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).…”