Rabbit Ocular Mucosal Immune System Contain CD4+CD25+ Regulatory T Cells That Control Local and Systemic Herpes Simplex Virus Type 1–Specific T Cell Response

Abstract

Purpose: : Fighting off the various invading pathogens that constantly attack the ocular surface requires a well–controlled pathogen–specific T–cell response, initiated locally at the ocular mucosal immune system (OMIS). Outside the OMIS, the ability to evoke systemic T cell responses, that are normally suppressed by naturally occurring CD4+CD25+ regulatory T–cells (CD4+CD25+ T reg), has been well documented. To date, there is no report on resident CD4+CD25+ T reg within the OMIS and the role they might play in controlling local ocular immune responses. The purpose of this study was to characterize resident T cells and APCs in normal conjunctiva, a major T cell inductive site of OMIS, and to investigate the role that conjunctiva–derived CD4+CD25+ T reg may play during ocular herpes simplex virus (HSV–1) infection and immunity.

Methods: : Conjunctiva, cornea, spleen and peripheral blood were harvested from normal and HSV–1 infected rabbits. CD45+ pan leukocytes were sorted and examined by FACS for resident effector and regulatory T cells and APCs. To assess their effect on local and systemic T cell stimulation; CD4+CD25+ T reg and CD4+CD25– non–T reg were isolated from normal conjunctiva and co–cultured in vitro with HSV–specific effector T cells, isolated from immune conjunctiva or PBMC.

Results: : Normal conjunctiva contained CD4+ and CD8+ effector T cells, CD4+CD25+ T reg, and CD11b+ and CD11c+ APCs. Surprisingly, CD4+CD25+ T cells were abundant in normal conjunctiva, compared to cornea, spleen and peripheral blood. Moreover, CD4+CD25+ T cells isolated from the normal conjunctiva suppressed HSV–specific T cell responses both locally within the conjunctiva and systemically within the peripheral blood.

Conclusions: : These findings shed new light on the immune cell composition and regulation within the OMIS and suggest that conjunctiva–resident CD4+CD25+ T reg cells play a role in controlling ocular mucosal T cell responses. These findings may open new ways to novel immunotherapeutic strategies against pathogens that invade the surface of the eye.

Keywords: herpes simplex virus • immunomodulation/immunoregulation • conjunctiva