Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist.
CD4(+)CD25(+) T cells play a central role in the suppression of autoimmunity and inflammation, making their in vivo expansion a highly attractive therapeutic target. By phenotyping with a novel rat CTL antigen-4 (CTLA-4)-specific monoclonal antibody (mAb) and functional in vitro assays, we here first establish that rat CD4(+)CD25(+) T cells correspond to the regulatory T cells (Treg cells) described in mice and humans: they constitutively express CTLA-4, produce IL-10 but not IL-2, and are able to suppress the proliferation of costimulated CD25-negative indicator cells. Furthermore, we show that rat Treg cells respond less well than CD25(-) T cells to conventional costimulation, but are readily expanded in vitro with "superagonistic" CD28-specific mAb which are potent mitogens for all T cells without the need for TCR engagement. In vivo, functional Treg cells are preferentially expanded by CD28 stimulation over other T cell subsets, leading to a 20-fold increase within 3 days in response to a single antibody dose. These data suggest that CD28-driven activation of Treg cells may be highly effective in the treatment of inflammatory and autoimmune diseases.
Lin
Chia-Huey
CH
Institute for Virology and Immunobiology, University of Würzburg, Versbacherstrasse 7, D-97078 Würzburg, Germany.
Hünig
Thomas
T
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis; D018106:CD28 Antigens / Q000502:physiology*; D015704:CD4 Antigens / Q000032:analysis; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D000069594:Abatacept