title: OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T cells into high IL-4-producing effectors.
abstract: Th2 cell development is critically dependent on the presence of interleukin-4 (IL-4) at priming. The cellular origin and the mechanisms regulating this early production of IL-4 at the site of naive T-cell priming are extensively investigated. We previously reported that anti-CD3-activated and CD28-costimulated naive human CD4(+) T cells themselves release very low but sufficient levels of IL-4 to support their development into high IL-4-producing cells. We show here that ligation of OX40 Ag, a member of the tumor necrosis factor receptor (TNF-R) family, on activated umbilical cord blood CD4(+) T cells upregulates IL-4 production at priming and thereby promotes their development into effector cells producing high levels of the type 2 cytokines IL-4, IL-5, and IL-13. OX40 ligation increases four times the expression of IL-4 mRNA after 48 hours of anti-CD3/B7.1 activation and significantly augments the release of IL-4 and IL-13 in primary cultures. The effects of OX40 costimulation on Th cell differentiation are observed in the presence of optimal and suboptimal CD28 stimulation. Because OX40 ligand is expressed on dendritic cells, the OX40 costimulation pathway may be involved in the physiological regulation of Th cell development by augmenting the differentiation of IL-4-producing cells.
authors.affiliation: University of Montreal, Centre de Recherche Louis-Charles Simard, Notre-Dame Hospital, and the Department of Obstetrics and Gynecology, Montreal, Quebec, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohshima
authors.forename: L P
authors.initials: LP
authors.lastname: Yang
authors.forename: T
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: P
authors.initials: P
authors.lastname: Baum
authors.forename: M
authors.initials: M
authors.lastname: Sergerie
authors.forename: P
authors.initials: P
authors.lastname: Hermann
authors.forename: G
authors.initials: G
authors.lastname: Delespesse
mesh_terms: D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015848:Interleukin-5 / Q000096:biosynthesis; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3 / Q000494:pharmacology; D053278:OX40 Ligand; D012333:RNA, Messenger / Q000096:biosynthesis; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology*
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D018793:Interleukin-13; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D053278:OX40 Ligand; D012333:RNA, Messenger; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D018664:Interleukin-12; D015847:Interleukin-4