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Novel genetic regulation of T helper 1 (Th1)/Th2 cytokine production and encephalitogenicity in inbred mouse strains.

Conboy IM, DeKruyff RH, Tate KM, Cao ZA, Moore TA, Umetsu DT, Jones PP - J. Exp. Med. (1997)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Stanford University, California 94305-5020, USA.

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.

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Modulation of downregulatory activity by addition or neutralization of known cytokine regulators during restimulation of B10.BR  T cells with either B10.BR or B10.A splenic APC. B10.BR T cells (TCL 4)  were restimulated with mMBP Ac1-16 and either B10.BR or B10.A  splenic APC for 24 h in the absence or presence of mouse recombinant  IL-4, IFN-γ, TNF-α, and IL-12 alone or combination with neutralizing  antibody specific for mouse IL-12, or mouse IL-4. Cytokine levels resulting from each treatment are expressed as a percentage of control (B10.BR  TCL, B10.BR APC, and peptide with no cytokine or antibody additions). Data presented are means and standard deviations of triplicate wells  for each sample (n = 3). At least two independent experiments were performed for each treatment, yielding similar results.
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Figure 6: Modulation of downregulatory activity by addition or neutralization of known cytokine regulators during restimulation of B10.BR T cells with either B10.BR or B10.A splenic APC. B10.BR T cells (TCL 4) were restimulated with mMBP Ac1-16 and either B10.BR or B10.A splenic APC for 24 h in the absence or presence of mouse recombinant IL-4, IFN-γ, TNF-α, and IL-12 alone or combination with neutralizing antibody specific for mouse IL-12, or mouse IL-4. Cytokine levels resulting from each treatment are expressed as a percentage of control (B10.BR TCL, B10.BR APC, and peptide with no cytokine or antibody additions). Data presented are means and standard deviations of triplicate wells for each sample (n = 3). At least two independent experiments were performed for each treatment, yielding similar results.

Mentions: As summarized in Fig. 6, blocking or adding IL-4 and IL-12 (alone or in combinations) did not reduce the downregulatory effects of B10.A APC on TNF-α levels, although there were effects on the absolute levels of TNF-α production. In contrast, adding IFN-γ significantly reduced the downregulation by B10.A APC. For IFN-γ production, adding TNF-α did not prevent the downregulation of IFN-γ by B10.A APC, and adding IL-4 did not synergize with this downregulation (Fig. 6 B). As expected because of their pro-Th1 effects, addition of IL-12 alone, or in combination with anti-IL-4, did increase the overall IFN-γ levels and reduced the downregulation of IFN-γ by B10.A APC.


Novel genetic regulation of T helper 1 (Th1)/Th2 cytokine production and encephalitogenicity in inbred mouse strains.

Conboy IM, DeKruyff RH, Tate KM, Cao ZA, Moore TA, Umetsu DT, Jones PP - J. Exp. Med. (1997)

Modulation of downregulatory activity by addition or neutralization of known cytokine regulators during restimulation of B10.BR  T cells with either B10.BR or B10.A splenic APC. B10.BR T cells (TCL 4)  were restimulated with mMBP Ac1-16 and either B10.BR or B10.A  splenic APC for 24 h in the absence or presence of mouse recombinant  IL-4, IFN-γ, TNF-α, and IL-12 alone or combination with neutralizing  antibody specific for mouse IL-12, or mouse IL-4. Cytokine levels resulting from each treatment are expressed as a percentage of control (B10.BR  TCL, B10.BR APC, and peptide with no cytokine or antibody additions). Data presented are means and standard deviations of triplicate wells  for each sample (n = 3). At least two independent experiments were performed for each treatment, yielding similar results.
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Related In: Results  -  Collection

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Figure 6: Modulation of downregulatory activity by addition or neutralization of known cytokine regulators during restimulation of B10.BR T cells with either B10.BR or B10.A splenic APC. B10.BR T cells (TCL 4) were restimulated with mMBP Ac1-16 and either B10.BR or B10.A splenic APC for 24 h in the absence or presence of mouse recombinant IL-4, IFN-γ, TNF-α, and IL-12 alone or combination with neutralizing antibody specific for mouse IL-12, or mouse IL-4. Cytokine levels resulting from each treatment are expressed as a percentage of control (B10.BR TCL, B10.BR APC, and peptide with no cytokine or antibody additions). Data presented are means and standard deviations of triplicate wells for each sample (n = 3). At least two independent experiments were performed for each treatment, yielding similar results.
Mentions: As summarized in Fig. 6, blocking or adding IL-4 and IL-12 (alone or in combinations) did not reduce the downregulatory effects of B10.A APC on TNF-α levels, although there were effects on the absolute levels of TNF-α production. In contrast, adding IFN-γ significantly reduced the downregulation by B10.A APC. For IFN-γ production, adding TNF-α did not prevent the downregulation of IFN-γ by B10.A APC, and adding IL-4 did not synergize with this downregulation (Fig. 6 B). As expected because of their pro-Th1 effects, addition of IL-12 alone, or in combination with anti-IL-4, did increase the overall IFN-γ levels and reduced the downregulation of IFN-γ by B10.A APC.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Stanford University, California 94305-5020, USA.

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.

Show MeSH
Related in: MedlinePlus