Mesenchymal stem cells augment regulatory T cell function via CD80‐mediated interactions and promote allograft survival

• Published in: American journal of transplantation Vol. 22; no. 6; pp. 1564 - 1577
• Main Authors: Mittal, Sharad K., Cho, WonKyung, Elbasiony, Elsayed, Guan, Yilin, Foulsham, William, Chauhan, Sunil K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.06.2022
• Subjects: Allografts; Animal models; Animals; basic (laboratory) research/science; CD80 antigen; Cell culture; Cell proliferation; Cornea; Corneal transplantation; corneal transplantation/ophthalmology; experimental; Forkhead Transcription Factors - metabolism; Foxp3 protein; immune regulation; Immunoregulation; Lymphocytes T; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Stem cell transplantation; Stem cells; Supplements; T-Lymphocytes, Regulatory; tolerance; Transplantation, Homologous; Transplants & implants; corneal transplantation/ophthalmology; experimental; immune regulation; tolerance; basic (laboratory) research/science
• ISSN: 1600-6135; 1600-6143; 1600-6143
• DOI: 10.1111/ajt.17001

Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) both have been shown to modulate the alloimmune response and promote transplant survival. Mounting evidence suggests that MSCs augment Treg function, but the mechanisms underlying this phenomenon have not been fully deciphered. Here, we identified that MSCs express substantial levels of CD80 and evaluated its immunoregulatory function using in vivo and in vitro experiments. Our in vitro culture assays demonstrated that MSCs induce expression of FoxP3 in Tregs in a contact‐dependent manner, and the blockade of CD80 abrogates this FoxP3 induction and Treg‐mediated suppression of T cell proliferation. Moreover, supplementation of soluble CD80 significantly upregulated FoxP3 expression. Using a well‐characterized murine model of corneal transplantation, we show that silencing CD80 in MSCs diminishes the capacity of MSCs to promote selective graft infiltration of Tregs, promote FoxP3 expression and upregulate suppressive function of Tregs. Consequently, MSCs, following CD80 knockdown, failed to promote corneal allograft survival. Loss‐of‐function approaches in a model of alloimmunity provides novel evidence that mesenchymal stem cell expression of CD80 is critical for direct interaction with regulatory T cells to augment FoxP3 expression, enhance suppressive function, and promote graft survival.