title: Common gamma chain cytokines promote rapid in vitro expansion of allo-specific human CD8+ suppressor T cells.
abstract: Human CD8(+) regulatory T cells, particularly the CD8(+)CD28(-) T suppressor cells, have emerged as an important modulator of alloimmunity. Understanding the conditions under which these cells are induced and/or expanded would greatly facilitate their application in future clinical trials. In the current study, we develop a novel strategy that combines common gamma chain (γc) cytokines IL-2, IL-7 and IL-15 and donor antigen presenting cells (APCs) to stimulate full HLA-mismatched allogeneic human CD8(+) T cells which results in significant expansions of donor-specific CD8(+)CD28(-) T suppressor cells in vitro. The expanded CD8(+)CD28(-) T cells exhibit increased expressions of CTLA-4, FoxP3, and CD25, while down-regulate expressions of CD56, CD57, CD127, and perforin. Furthermore, these cells suppress proliferation of CD4(+) T cells in a contact-dependent and cytokine-independent manner. Interestingly, the specificity of suppression is restricted by the donor HLA class I antigens but promiscuous to HLA class II antigens, providing a potential mechanism for linked suppression. Taken together, our results demonstrate a novel role for common γc cytokines in combination with donor APCs in the expansion of donor-specific CD8(+)CD28(-) T suppressor cells, and represent a robust strategy for in vitro generation of such cells for adoptive cellular immunotherapy in transplantation.
authors.affiliation: Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Yu
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Zitzner
authors.forename: Josetta
authors.initials: J
authors.lastname: Houlihan
authors.forename: Nancy
authors.initials: N
authors.lastname: Herrera
authors.forename: Luting
authors.initials: L
authors.lastname: Xu
authors.forename: Joshua
authors.initials: J
authors.lastname: Miller
authors.forename: James M
authors.initials: JM
authors.lastname: Mathew
authors.forename: Anat R
authors.initials: AR
authors.lastname: Tambur
authors.forename: Xunrong
authors.initials: X
authors.lastname: Luo
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D000939:Epitopes / Q000187:drug effects / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism*; D010641:Phenotype; D013045:Species Specificity; D014019:Tissue Donors; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D053631:Interleukin Receptor Common gamma Subunit; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma