title: CTLA-4 x Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells.
abstract: CTLA-4 x Ig was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4 x Ig, in combination with TCR ligation, has the additional capacity to convert naive CD4+CD25- T cells into Foxp3+ regulatory T (T(reg)) cells, as well as to expand their numbers. The CD4+CD25+Foxp3+ T(reg) generated by CTLA-4 x Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4 x Ig increases the percentage of CD4+CD25(hi)Foxp3+ cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4+CD25- T cells into T(reg) cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4 x Ig-driven T(reg) induction may be predicated upon active CTLA-4 x Ig to B7-2 signaling within APC, which elicits from them T(reg)-inducing potential. These findings extend CTLA-4 x Ig's functional repertoire, and at the same time, reinforce the concept that T cell anergy and active suppression are not entirely distinct processes and may be linked by some common molecular triggers.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA.
authors.forename: Marjaneh
authors.initials: M
authors.lastname: Razmara
authors.forename: Brendan
authors.initials: B
authors.lastname: Hilliard
authors.forename: Azadeh K
authors.initials: AK
authors.lastname: Ziarani
authors.forename: Youhai H
authors.initials: YH
authors.lastname: Chen
authors.forename: Mark L
authors.initials: ML
authors.lastname: Tykocinski
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D000937:Antigen-Antibody Reactions; D015703:Antigens, CD / Q000494:pharmacology*; D015704:CD4 Antigens / Q000096:biosynthesis; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D007136:Immunoglobulins / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007136:Immunoglobulins; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger