Allogeneic ADSCs induce CD8 T cell-mediated cytotoxicity and faster cell death after exposure to xenogeneic serum or proinflammatory cytokines

Sung-Ho Chang,Chung-Gyu Park

doi:10.1038/s12276-019-0231-5

Abstract

This study examined the induction of recipient T-cell cytotoxicity after exposure to allogeneic adipose-derived mesenchymal stem cells (ADSCs). ADSCs pre-exposed to xenogeneic serum significantly induced cytotoxicity through CD8 T-cell granzyme B secretion after allogeneic antigen stimulation, and this effect was increased with prolonged reaction time. ADSCs pretreated with proinflammatory cytokines also induced cytotoxicity through granzyme B secretion and significantly increased human leukocyte antigen (HLA)-ABC expression. T-cell cytotoxicity towards ADSCs grown in xeno-free medium (XF-ADSCs) was lower than that towards ADSCs exposed to xenogeneic serum or proinflammatory cytokines, but XF-ADSCs still induced cytotoxicity. We further investigated the causes of T-cell cytotoxicity towards XF-ADSCs. XF-ADSC death was effectively inhibited by HLA-blocking antibodies, suggesting that ADSC HLAs are a major cause of alloreactive T-cell generation. These results indicated that culturing of allogeneic ADSCs with recipient serum may alleviate alloreactive CD8 T-cell cytotoxicity. Ultimately, development of therapeutic agents using autologous ADSCs would be a suitable way to avoid immunogenicity and CD8 T cell-mediated cytotoxicity, but more attention should be paid to the potential immunogenicity of allogeneic ADSCs, which could perhaps be mitigated through the use of immunosuppressants.

Highlights

Human mesenchymal stem cells (MSCs) proliferate and differentiate in response to signals in their surrounding environment and display immunomodulating, angiogenic, and self-renewing abilities
We used adipose-derived mesenchymal stem cells (ADSCs) cultured under the following two conditions for allogeneic antigen stimulation in an ex vivo immunogenicity assessment model: (1) ADSCs cultured in xeno-free medium immediately after isolation from adipose tissue (XF-ADSCs), and (2) ADSCs cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing fetal bovine serum (FBS) that were washed with Dulbecco’s phosphate-buffered saline (DPBS) 1 or 3 days before allogeneic antigen stimulation, at which time the medium was replaced with xeno-free medium
Allogeneic XF-ADSCs pretreated with proinflammatory cytokines induce greater CD8 T cell-mediated cytotoxicity than untreated XF-ADSCs We investigated the effects of the recipient T cells on allogeneic XF-ADSCs pretreated with IFN-γ, IL-17, and IL-23 complexes in xeno-free medium 3 days prior to allogeneic antigen stimulation

Summary

Introduction

Human mesenchymal stem cells (MSCs) proliferate and differentiate in response to signals in their surrounding environment and display immunomodulating, angiogenic, and self-renewing abilities. They have attracted attention as potential therapeutic agents for cardiac, neurological, orthopedic, digestive, and immune diseases[1,2,3,4]. MSCs are thought to possess no or low immunogenicity in allografts[10,11,12]. There is a concern that allogeneic MSCs may be immunogenic due to the expression of allogeneic antigens at the allograft[15,16,17,18,19,20,21,22,23,24].

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