Human HLA-DR+CD27+ regulatory T cells show enhanced antigen-specific suppressive function

Ma, X; Cao, L; Raneri, M; Wang, H; Cao, Q; Zhao, Y; Bediaga, NG; Naselli, G; Harrison, LC; Hawthorne, WJ; Hu, M; Yi, S; O&#39;Connell, PJ

Author(s): Ma, X; Cao, L; Raneri, M; Wang, H; Cao, Q; Zhao, Y; Bediaga, NG; Naselli, G; Harrison, LC; Hawthorne, WJ; Hu, M; Yi, S; O'Connell, PJ;
Journal Title: JCI Insight
Abstract: Regulatory T cells (Treg) have potential for the treatment of autoimmune diseases and graft rejection. Antigen-specificity and functional stability are considered to be critical for their therapeutic efficacy. In this study, expansion of human Treg in the presence of porcine PBMC (Xn-Treg) allowed the selection of a distinct Treg subset, co-expressing the activation/memory surface markers HLA-DR and CD27 with enhanced proportion of FOXP3+Helios+ Tregs. Compared to their unsorted and HLA-DA+CD27+ double positive (DP) cell depleted Xn-Treg counterparts, HLA-DR+CD27+ DP-Enriched Xn-Treg expressed upregulated Treg function markers CD95 and ICOS with enhanced suppression of xenogeneic but not polyclonal MLR. They also had less methylated Treg-specific demethylated region (TSDR) of FOXP3 and were more resistant to conversion to effector cells under inflammatory conditions. Adoptive transfer of porcine islet recipient NOD-SCID IL2 receptor γ-/- (NSG) mice with HLA-DR+CD27+ DP-Enriched Xn-Treg in a humanized mouse model inhibited porcine islet graft rejection mediated by 25-fold more human effector cells. The prolonged graft survival was associated with enhanced accumulation of FOXP3+ Treg and upregulated expression of Treg functional genes, IL10 and CTLA4, but downregulated expression of effector Th1, Th2, and Th17 cytokine genes, within surviving grafts. Collectively, human HLA-DR+CD27+ DP-Enriched Xn-Treg expressed a specific regulatory signature that enabled identification and isolation of antigen-specific and functionally stable Treg with potential as a Treg-based therapy.
Publisher: ASCI
Keywords: Immunology; Immunotherapy; T cells; Tolerance; Transplantation
Research Division(s): Population Health And Immunity
PubMed ID: 37874660
Publisher's Version: https://doi.org/10.1172/jci.insight.162978
Open Access at Publisher's Site: https://doi.org/10.1172/jci.insight.162978
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-15 05:00:11

Last Modified: 2023-12-13 10:19:49