title: Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells.
abstract: Although recent studies have focused on CD4(+) regulatory T cells (Treg), CD8(+) Treg have also been reported to play important roles in the induction and maintenance of immune tolerance. Adoptive transfer of CD8(+) Treg in rodents or induction of CD8(+) Treg in humans can prevent or treat allograft rejection and autoimmune diseases. However, no approaches have been reported for the generation of human Ag-specific CD8(+) Treg at a practical scale for clinical use. Here, we found that two novel CD8(+) T cell subsets with different levels of CD8 surface expression, CD8(high) and CD8(low), could be induced from naive CD8(+) precursors in vitro by allogeneic CD40-activated B cells, whereas only CD8(high) T cells were alloantigen-specific Treg with relatively poor alloantigen-specific cytotoxicity. Importantly, alloantigen-specific CD8(high) Treg could be induced and expanded from naive CD8(+)CD25(-) T cells at a large scale after 3 wk of culture without exogenous cytokines. These induced alloantigen-specific Treg were CD45RO(+) and CCR7(-) memory cells, and they expressed Foxp3, CD25, CD27, CD28, and CD62L. The induction and expansion of CD8(high) Treg by CD40-activated B cells were dependent on endogenously expressed IFN-gamma, IL-2, IL-4, and CTLA-4. This approach may facilitate the clinical application of CD8(+) Treg-based immunotherapy in transplantation and autoimmune diseases.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Yinping
authors.initials: Y
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Qin
authors.forename: Ping-Lung
authors.initials: PL
authors.lastname: Chan
authors.forename: Huawei
authors.initials: H
authors.lastname: Mao
authors.forename: Kwok-Tai
authors.initials: KT
authors.lastname: Lam
authors.forename: David B
authors.initials: DB
authors.lastname: Lewis
authors.forename: Yu-Lung
authors.initials: YL
authors.lastname: Lau
authors.forename: Wenwei
authors.initials: W
authors.lastname: Tu
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018929:Cell Culture Techniques; D019070:Cell Lineage / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D013234:Stem Cells / Q000166:cytology; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology
chemical_list: D015703:Antigens, CD; D019013:CD40 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007519:Isoantigens