Augmented Expansion of Treg Cells From Healthy and Autoimmune Subjects via Adult Progenitor Cell Co-Culture

• Published in: Frontiers in immunology Vol. 12; p. 716606
• Main Authors: Reading, James L, Roobrouck, Valerie D, Hull, Caroline M, Becker, Pablo Daniel, Beyens, Jelle, Valentin-Torres, Alice, Boardman, Dominic, Lamperti, Estefania Nova, Stubblefield, Samantha, Lombardi, Giovanna, Deans, Robert, Ting, Anthony E, Tree, Timothy
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 01.09.2021
• Subjects: adult progenitor cells; Adult Stem Cells - cytology; Adult Stem Cells - immunology; Adult Stem Cells - metabolism; Animals; autoimmune diseases; Autoimmune Diseases - etiology; Autoimmune Diseases - metabolism; Autoimmune Diseases - pathology; Autoimmunity; Biomarkers; Cells, Cultured; co-culture; Coculture Techniques; Disease Models, Animal; Disease Susceptibility; ex vivo expansion; Female; Gene Expression Regulation; Graft vs Host Disease - diagnosis; Graft vs Host Disease - etiology; Humans; Immunology; Immunophenotyping; Lymphocyte Count; Male; Mice; regulatory T (Treg) cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; autoimmune diseases; regulatory T (Treg) cells; adult progenitor cells; co-culture; ex vivo expansion
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.716606

Recent clinical experience has demonstrated that adoptive regulatory T (Treg) cell therapy is a safe and feasible strategy to suppress immunopathology induction of host tolerance to allo- and autoantigens. However, clinical trials continue to be compromised due to an inability to manufacture a sufficient Treg cell dose. Multipotent adult progenitor cells (MAPC ) promote Treg cell differentiation , suggesting they may be repurposed to enhance expansion of Tregs for adoptive cellular therapy. Here, we use a Good Manufacturing Practice (GMP) compatible Treg expansion platform to demonstrate that MAPC cell-co-cultured Tregs (MulTreg) exhibit a log-fold increase in yield across two independent cohorts, reducing time to target dose by an average of 30%. Enhanced expansion is coupled to a distinct Treg cell-intrinsic transcriptional program characterized by elevated expression of replication-related genes ( ), downregulation of progenitor and lymph node-homing molecules ( ) and induction of intestinal and inflammatory tissue migratory markers ( ) consistent with expression of a gut homing (CCR7lo β hi) phenotype. Importantly, we find that MulTreg are more readily expanded from patients with autoimmune disease compared to matched Treg lines, suggesting clinical utility in gut and/or T helper type1 (Th1)-driven pathology associated with autoimmunity or transplantation. Relative to expanded Tregs, MulTreg retain equivalent and robust purity, FoxP3 Treg-Specific Demethylated Region (TSDR) demethylation, nominal effector cytokine production and potent suppression of Th1-driven antigen specific and polyclonal responses and xeno Graft vs Host Disease (xGvHD) . These data support the use of MAPC cell co-culture in adoptive Treg therapy platforms as a means to rescue expansion failure and reduce the time required to manufacture a stable, potently suppressive product.