Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells.
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.
Zheng
Jian
J
Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, People's Republic of China.
Liu
Yinping
Y
Qin
Gang
G
Chan
Ping-Lung
PL
Mao
Huawei
H
Lam
Kwok-Tai
KT
Lewis
David B
DB
Lau
Yu-Lung
YL
Tu
Wenwei
W
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
D015703:Antigens, CD; D019013:CD40 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007519:Isoantigens