title: The capacity of the natural ligands for CD28 to drive IL-4 expression in naïve and antigen-primed CD4+ and CD8+ T cells.
abstract: The B7/CD28 costimulatory pathway plays a critical role in T cell activation including Th1/Th2 differentiation. However, little is known about whether CD28 costimulation favors polarization of either Th1 and Th2 or both. Here, we show a critical role of the natural ligands for CD28 molecules (B7.2-Ig or B7.1-Ig fusion proteins), particularly in the induction of type 2 T cell polarization. Upon TCR-triggering with suboptimal doses of anti-CD3, costimulation of naïve CD4+ T cells with anti-CD28 mAb or B7-Ig fusion proteins led to comparable levels of IFN-gamma production. Naïve T cells could produce IL-4 when CD28 costimulation was done with B7-Ig, but not with anti-CD28. IL-4-selective upregulation was also observed when T cells from anti-OVA TCR transgenic mice were stimulated with OVA in the presence of B7-Ig. Correlating with IL-4 expression, GATA-3 expression was induced much more potently by costimulation with B7-Ig than with anti-CD28 mAb, while T-bet induction by these two costimulatory reagents was comparable. This B7 effect was also applied for naïve and antigen-primed CD8+ T cells: IL-4-expressing CD8+ T cells were generated when naïve and alloantigen-primed T cells were stimulated with anti-CD3 and recall antigens, respectively, in the presence of B7-Ig costimulation. Importantly, such CD8+ T cell differentiation required the coexistence of CD4+ T cells during the initial TCR stimulation. These observations indicate that both type 2 CD4 and CD8 T cell polarizations are efficiently induced via costimulation of CD28 with its natural ligands, although the differentiation of CD8+ T cells is dependent on CD4+ cells.
authors.affiliation: Department of Oncology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bian
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Hiraoka
authors.forename: Michio
authors.initials: M
authors.lastname: Tomura
authors.forename: Xu-Yu
authors.initials: XY
authors.lastname: Zhou
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yashiro-Ohtani
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mori
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.forename: Shiro
authors.initials: S
authors.lastname: Ono
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Dunussi-Joannopoulos
authors.forename: Stanley
authors.initials: S
authors.lastname: Wolf
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology; D015703:Antigens, CD / Q000494:pharmacology / Q000502:physiology*; D018122:B7-1 Antigen / Q000494:pharmacology / Q000502:physiology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000494:pharmacology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor; D015870:Gene Expression / Q000187:drug effects; D007074:Immunoglobulin G / Q000494:pharmacology / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000502:physiology; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007074:Immunoglobulin G; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma