A crucial role for B and T lymphocyte attenuator in preventing the development of CD4+ T cell-mediated herpetic stromal keratitis

[摘要] Purpose: To investigate the effect ofthe B and T lymphocyte attenuator (BTLA; CD272) on cluster ofdifferentiation (CD)4+ T cell-mediated cornealimmunopathology during murine herpetic stromal keratitis (HSK). Methods: BALB/c mice were infected withthe herpes simplex virus type 1 (HSV-1) KOS strain by cornealscarification. The levels of BTLA expression in CD4+ and CD8+T cells in murine peripheral blood were determined by flow cytometry ondays 0, 3, 7, 10, 14, and 21 after HSV-1 infection. BTLA expression inthe infected cornea was detected by immunohistochemistry. BALB/c micewere injected intraperitoneally with recombinant plasmid DNA encodingBTLA (pBTLA), pcDNA3.1, or PBS on 0 and 7 days before infection and 7days postinfection. The incidence and severity of stromal disease, tearfilm virus titers, and the delayed-type hypersensitivity (DTH) reactionwere then compared among treated and control groups. The effects ofpBTLA on CD4+ T cells that infiltrated into infected corneasand on type 1 helper T-cell (Th1) cytokines (interferon-gamma [IFN-γ])were evaluated. The levels of glycoprotein D (gD) mRNA incorneas were tested by real-time PCR. The eyes were examinedhistologically. Results: BTLA expression increased bothin the corneas of HSV-1 infected mice and in CD4+ T cells inthe murine peripheral blood. Systemic administration of pBTLA resultedin a diminished incidence and severity of corneal lesions compared tocontrols. Treatment with pBTLA led to a decreased infiltration of CD4+T cells into infected corneas, and diminished Th1 responses in murinecorneas, draining lymph nodes, and splenocytes. The pBTLA treated miceshowed an impaired DTH response two weeks after HSV-1 infectioncompared to control mice. No differences were noted in tear film virustiters or gD mRNA levels in corneas among the experimentalgroups. Conclusions: The results suggest thatrecombinant pBTLA plays a crucial role in preventing HSV-1 specificresponses in CD4+ Th1 cells in the infected corneas. Thus,BTLA, with immunosuppressive effects, may be a good candidate fortreatment of HSK.

[学科分类] 生物化学/生物物理