Retinal Pigment Epithelial Cells Derived from Induced Pluripotent Stem (iPS) Cells Suppress or Activate T Cells via Costimulatory Signals.

Sunao Sugita,Ayaka Edo,Masaaki Ishida,Yoko Futatsugi,Masayo Takahashi

doi:10.3390/ijms21186507

Abstract

Human retinal pigment epithelial (RPE) cells derived from induced pluripotent stem (iPS) cells have immunosuppressive properties. However, RPE cells are also known as immunogenic cells, and they have major histocompatibility complex expression and produce inflammatory proteins, and thus experience immune rejection after transplantation. In this study, to confirm the immunological properties of IPS-RPE cells, we examined whether human RPE cells derived from iPS cells could suppress or stimulate inflammatory T cells from uveitis patients via costimulatory signals. We established T cells from patients with active uveitis as target cells and used iPS-RPE cells as effector cells. As a result, cultured iPS-RPE cells inhibited cell proliferation and the production of IFN-γ by activated uveitis CD4+ T cells, especially Th1-type T cells. In contrast, iPS-RPE cells stimulated T cells of uveitis patients. The iPS-RPE cells constitutively expressed B7-H1/CD274 and B7-DC/CD273, and suppressed the activation of T cells via the PD-1 receptor. iPS-RPE expressed these negative costimulatory molecules, especially when RPE cells were pretreated with recombinant IFN-γ. In addition, iPS-RPE cells also expressed B7-H3/CD276 costimulatory molecules and activated uveitis T cells through the B7-H3-TLT-2 receptor. Thus, cultured iPS-derived retinal cells can suppress or activate inflammatory T cells in vitro through costimulatory interactions.

Highlights

Uveitis is a typical ocular inflammatory disease, and many uveitis patients are currently undergoing treatment
In this study, we examined whether human Retinal pigment epithelial (RPE) cells derived from induced pluripotent stem cells could suppress or stimulate uveitis T cells via costimulatory signals. iPS cell-derived RPE cells constitutively express negative costimulatory molecules such as B7-H1/CD274/programmed death-ligand 1 (PD-L1) or B7-DC/CD273/PD-L2, which can alter the expression of adaptive immune effector mechanisms in vitro
We first tested whether IPS-Derived RPE (iPS-RPE) cells could suppress intraocular T cells established from the peripheral blood mononuclear cells (PBMC) of patients with active uveitis

Summary

Introduction

Uveitis is a typical ocular inflammatory disease, and many uveitis patients are currently undergoing treatment. It has been speculated that the mechanism of spontaneous remission of inflammation is due to immune privilege in the eye [1,2,3]. RPE cells express and produce a suppressive cytokine, transforming growth factor beta (TGFβ), to suppress T cells [9,10,11], while expressing and producing various inflammation-related factors. Representatives of the latter are complements [12,13,14], inflammatory chemokines such as CXCL9/10/11 [15], adhesion molecules such as CD54/ICAM1 [16], and MHC class I/II [17,18]. There are reports that RPE cells express costimulatory molecules [19,20], but the details of the mechanism behind this are still unknown

Methods

Results

Conclusion