title: Genetic regulation of commitment to interleukin 4 production by a CD4(+) T cell-intrinsic mechanism.
abstract: The dysregulated expression of interleukin 4 (IL-4) can have deleterious effects on the outcome of infectious and allergic diseases. Despite this, the mechanisms by which naive T cells commit to IL-4 expression during differentiation into mature effector cells remain incompletely defined. As compared to cells from most strains of mice, activated CD4(+) T cells from BALB mice show a bias towards IL-4 production and T helper 2 commitment in vitro and in vivo. Here, we show that this bias arises not from an increase in the amount of IL-4 produced per cell, but rather from an increase in the proportion of CD4(+) T cells that commit to IL-4 expression. This strain-specific difference in commitment was independent of signals mediated via the IL-4 receptor and hence occurred upstream of potential autoregulatory effects of IL-4. Segregation analysis of the phenotype in an experimental backcross cohort implicated a polymorphic locus on chromosome 16. Consistent with a role in differentiation, expression of the phenotype was CD4(+) T cell intrinsic and was evident as early as 16 h after the activation of naive T cells. Probabilistic gene activation is proposed as a T cell-intrinsic mechanism capable of modulating the proportion of naive T cells that commit to IL-4 production.
authors.affiliation: Departments of Medicine and Microbiology/Immunology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bix
authors.forename: Z E
authors.initials: ZE
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Thiel
authors.forename: N J
authors.initials: NJ
authors.lastname: Schork
authors.forename: R M
authors.initials: RM
authors.lastname: Locksley
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D002678:Chimera / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D008040:Genetic Linkage; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D019041:L-Selectin / Q000032:analysis; D008099:Liver / Q000166:cytology / Q000196:embryology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D007378:Interleukins; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D019041:L-Selectin; D015847:Interleukin-4