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

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.

Soluble Collectin 11 (CL-11) Acts as an Immunosuppressive Molecule Potentially Used by Stem Cell-Derived Retinal Epithelial Cells to Modulate T Cell Response

“…Due to the ability of fRPE cells to express HLA-DR molecules following IFN-γ exposure, we focused on the CD4+ T cell subset ( Supplementary Figure S2A ) and analyzed their proliferation and cytokine production. It has been recently shown that cultured RPE cells can suppress or activate T cells in vitro [ 41 ]. Therefore, we first co-cultured fRPE cells with PBMCs in the absence of other exogenous stimuli to test their ability to promote a T cell response.…”

Investigation of the effectiveness of gelatin hydrolysate in human iPS-RPE cell suspension transplantation

“…In light of the immunogenic nature of RPE cells, strategies aimed at mitigating intraocular inflammation following transplantation need to be considered [ 28 ]. Previous reports have shown that ROCK inhibitors exert immunosuppressive effects, including suppressing allogeneic immune responses and graft-versus-host disease [ [29] , [30] , [31] ] [ [29] , [30] , [31] ] [ [29] , [30] , [31] ].…”

A ROCK Inhibitor Promotes Graft Survival during Transplantation of iPS-Cell-Derived Retinal Cells

“…As shown in our in vitro assays, MHC class II on RPE cells was downregulated by Y-27632, suggesting that immune rejection of a graft would be reduced by Y-27632. Since RPE cells exhibit immunogenic properties [ 29 ], we have to consider how to reduce intraocular inflammation after transplantation. To test the effect of Y-27632 against immune rejection, further in vivo experiments will be required to see whether administration of Y-27632 during transplantation allows for fewer or no immunosuppressants.…”