title: Novel genetic regulation of T helper 1 (Th1)/Th2 cytokine production and encephalitogenicity in inbred mouse strains.
abstract: Development of T helper cell (Th)1 or Th2 cytokine responses is essential for effector and regulatory functions of T helper cells. We have compared cytokine profiles of myelin basic protein (MBP) Ac1-16 peptide-specific T helper cells from inbred mouse strains expressing identical k haplotype-derived MHC class II molecules B10.A and B10.BR, B10.BR T cell lines (TCL) produced Th1 cytokines (including high levels of TNF-alpha) and induced experimental autoimmune encephalomyelitis after adoptive transfer. In contrast, B10.A TCL produced Th2 cytokines (including low levels of TNF-alpha) and were poorly encephalitogenic. The contributions of the genetic origin of the T cells and the APC were explored. Serial restimulations of the B10.BR TCL with B10.A or (B10.A x B10.BR) F1 splenic antigen presenting cells (APC) during the establishment of TCL markedly reduced both Th1 cytokine production and encephalitogenicity. In addition, a single restimulation with B10. A splenic APC reduced IFN-gamma and TNF-alpha production by established Th1 MBP-specific Ak-restricted B10.BR TCL and by a Th1 KLH-specific, Ek-restricted B10.BR T cell clone. These studies suggest that B10.A and B10.BR APC differ in their ability to stimulate IFN-gamma and TNF-alpha production by mature Th1 cells and also influence their Th1/Th2 commitment in vivo. The nature of the downregulatory activity of B10.A APC on IFN-gamma and TNF-alpha production was explored. 2-hour supernatants from antigen-activated B10.A APC/TCL cultures or from B10.A APC activated by LPS had the same inhibitory effects on IFN-gamma and TNF-alpha production by B10.BR TCL. The downregulatory effects of B10.A APC are independent of TNF-alpha, IL-4, IL-10, IL-12p40, IFN-gamma, IL-13, TGF-beta, and PGE2. Thus, genetic difference(s) between B10.A and B10.BR APC appear(s) to control the production or activity of a novel soluble cytokine regulatory factor that influences Th1/Th2 commitment and controls production of IFN-gamma and TNF-alpha by mature Th1 cells.
authors.affiliation: Department of Biological Sciences, Stanford University, California 94305-5020, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Conboy
authors.forename: R H
authors.initials: RH
authors.lastname: DeKruyff
authors.forename: K M
authors.initials: KM
authors.lastname: Tate
authors.forename: Z A
authors.initials: ZA
authors.lastname: Cao
authors.forename: T A
authors.initials: TA
authors.lastname: Moore
authors.forename: D T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: P P
authors.initials: PP
authors.lastname: Jones
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology; D013045:Species Specificity; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D004676:Myelin Basic Protein; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma