Expression and function of the OX40/OX40L costimulatory pair during herpes stromal keratitis

Andrew J. Lepisto^*^,, Min Xu, Hideo Yagita, Andrew D. Weinberg^|| and Robert L. Hendricks^*^,¶^,#^,1

Departments of
^* Ophthalmology,
^¶ Immunology, and
^# Molecular Genetics and Biochemistry and
Graduate Program in Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA;
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; and
^|| Earl A. Chiles Research Institute, Providence Medical Center, Portland, Oregon, USA

¹ Correspondence: Eye and Ear Institute, 203 Lothrop Street, Room 922, Pittsburgh, PA 15213, USA. E-mail: hendricksrr{at}upmc.edu

Herpes stromal keratitis (HSK) is an immunopathological diseaseregulated by Th1 CD4 T cells, which require APC and costimulationwithin the infected cornea to mediate disease. Recent studiessuggest the OX40:OX40 ligand (OX40L) interaction enhances effectorcell cytokine secretion at inflammatory sites. OX40⁺ cells weredetected in HSV-1-infected mouse corneas as early as 3 dayspostinfection (dpi), prior to the onset of HSK, and their frequencyincreased through 15 dpi, when all mice exhibited severe HSK.OX40L⁺ cells were first detected at 7 dpi, coincident with theinitiation of HSK. It is interesting that the OX40L⁺ cells didnot coexpress MHC Class II or the dendritic cell (DC) markerCD11c. Our findings demonstrate rapid infiltration of activated(OX40⁺) CD4⁺ T cells into HSV-1-infected corneas and expressionof OX40L on MHC Class II-negative cells but surprisingly, noton MHC Class II⁺ CD11c⁺ DC, which are present in the infectedcorneas and required for HSK. Moreover, neither local nor systemictreatment of mice with a blocking antibody to OX40L or witha blocking fusion protein altered the course of HSK significantly,possibly as a result of a lack of OX40L expression on functionalAPC.

Key Words: HSV-1 • CD4 • mouse • cornea • immunopathology