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B.S. Kwon, H.Y. Park, J.H. Choi, W.Y. Kim, H.W. Jung, B. Kwon, S.K. Seo; Blocking 4-1BB/4-1BBL Interactions Prevents Herpetic Stromal Keratitis . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4189.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Herpetic stromal keratitis (HSK) is an autoimmune inflammatory process in corneal stroma that results from recurrent herpes simplex virus type 1 infection. We used the murine model of herpetic stromal keratitis to demonstrate the importance of the interaction between an inducible T cell costimulatory receptor, 4-1BB, and its ligand, 4-1BBL, in the development of this disease. Methods: HSK was induced by infection with the RE strain of HSV-1. To block the interaction between 4-1BB and 4-1BBL, either 4-1BB KO mice or blocking monoclonal antibodies against 4-1BBL were used. FACS and immunohistochemistry were used to analyze the T cells infiltrating into corneal stroma. RT-PCR and RNase protection assays were used to analyze the cytokine and chemokine mRNAs that were expressed in corneal stroma. Results: HSK was prevented when the interaction between 4-1BB and 4-1BBL was blocked by deleting 4-1BB or by introducing monoclonal antibodies against 4-1BBL. The majority of T cells infiltrating the infected corneas were 4-1BB+ activated effector T cells that expressed cell surface markers CD44, CD25, and CD62L, as well as chemokine receptors CCR1, CCR2, and CCR5 and a limited number of T cell receptor Vß chains (Vß8.1/8.2, Vß8.3, Vß10b, and Vß5.1/5.2 in order of abundance). Analysis of cell surface phenotypes showed that the failure to develop HSK in the 4-1BB-/- mice was associated with a reduced expression of CD62L at the time of T cell migration into the corneal stroma. Conclusions: HSK can be prevented by blocking the activities of the inducible costimulatory receptor 4-1BB. CD62L expression was reduced when 4-1BB/4-1BB ligand interaction was blocked. The reduced level of CD62L expression was associated with the failure of T cell infiltration into corneal stroma.
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