title: Therapeutic polyclonal human CD8+ CD25+ Fox3+ TNFR2+ PD-L1+ regulatory cells induced ex-vivo.
abstract: We report that polyclonal CD8regs generated in one week ex-vivo with anti-CD3/28 beads and cytokines rapidly developed suppressive activity in vitro sustained by TGF-β. In immunodeficient mice, these CD8regs demonstrated a markedly protective, IL-10 dependent activity against a xeno-GVHD. They expressed IL-2Rα/β, Foxp3, TNFR2, and the negative co-stimulatory receptors CTLA-4, PD-1, PD-L1 and Tim-3. Suppressive activity in vitro correlated better with TNFR2 and PD-L1 than Foxp3. Blocking studies suggested that TNF enhanced PD-L1 expression and the suppressive activity of the CD8regs generated. Unlike other polyclonal CD4 and CD8 Tregs, these CD8regs preferentially targeted allogeneic T cells, but they lacked cytotoxic activity against them even after sensitization. Unlike CD4regs, these CD8regs could produce IL-2 and proliferate while inhibiting target cells. If these CD8regs can persist in foreign hosts without impairing immune surveillance, they could serve as a practical remission-inducing product for the treatment of autoimmune diseases, graft-versus-host disease, and allograft rejection.
authors.affiliation: Division of Rheumatology, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. Electronic address: dhorwitz@usc.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pan
authors.forename: Jing-Ni
authors.initials: JN
authors.lastname: Ou
authors.forename: Julie
authors.initials: J
authors.lastname: Wang
authors.forename: Maogen
authors.initials: M
authors.lastname: Chen
authors.forename: J Dixon
authors.initials: JD
authors.lastname: Gray
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000276:immunology; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D053645:Interleukin-2 Receptor alpha Subunit; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha
keywords: Cell-based immunotherapy; IL-2; PDL1; Polyclonal CD8+ regulatory T cells; TGF-beta; TNFR2