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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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Supernatant from  B10.A T cells activated with  B10.A APC for 2 h downregulates IFN-γ and TNF-α production by B10.BR Th1 cells when  Ak-expressing L cell fibroblasts  are used as APC. B10.BR (top  bars) or B10.A (bottom bars) TCL  4 were activated with mMBP  Ac1-16 and Ak-expressing L cell  fibroblasts as APC for two consecutive restimulations in either  normal medium or in 2-h supernatants from B10.BR or B10.A  T cells activated with syngeneic  splenic APC. Culture supernatants were harvested 24 h after  restimulation and IFN-γ, TNF-α,  and IL-4 were measured as  above. Data presented are means  and standard deviations of triplicate wells for each sample (n =  3). Similar results were obtained  in two additional experiments.
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Figure 4: Supernatant from B10.A T cells activated with B10.A APC for 2 h downregulates IFN-γ and TNF-α production by B10.BR Th1 cells when Ak-expressing L cell fibroblasts are used as APC. B10.BR (top bars) or B10.A (bottom bars) TCL 4 were activated with mMBP Ac1-16 and Ak-expressing L cell fibroblasts as APC for two consecutive restimulations in either normal medium or in 2-h supernatants from B10.BR or B10.A T cells activated with syngeneic splenic APC. Culture supernatants were harvested 24 h after restimulation and IFN-γ, TNF-α, and IL-4 were measured as above. Data presented are means and standard deviations of triplicate wells for each sample (n = 3). Similar results were obtained in two additional experiments.

Mentions: To begin to clarify the target of action of the B10.A-derived regulatory factor, B10.BR or B10.A T cells (TCL 4) were restimulated twice with mMBP Ac1-16 presented by nonprofessional APC (Ak-expressing L cells which do not produce splenic APC-derived cytokines), in the presence of 2-h supernatant from B10.A cultures. In either normal medium or in the 2-h B10.BR supernatant, B10.BR T cells produced high levels of IFN-γ and TNF-α, and B10.A T cells produced high levels of IL-4 with little or no TNF-α and IFN-γ. However, the levels of IFN-γ and TNF-α produced by B10.BR TCL were reduced in the presence of 2-h supernatant from B10.A cultures, similar to the effects seen when professional splenic APC were used (Fig. 4). This result indicates that B10.A-derived factor does not require the presence of splenic APC for its action and probably acts directly on the responding T cells.


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)

Supernatant from  B10.A T cells activated with  B10.A APC for 2 h downregulates IFN-γ and TNF-α production by B10.BR Th1 cells when  Ak-expressing L cell fibroblasts  are used as APC. B10.BR (top  bars) or B10.A (bottom bars) TCL  4 were activated with mMBP  Ac1-16 and Ak-expressing L cell  fibroblasts as APC for two consecutive restimulations in either  normal medium or in 2-h supernatants from B10.BR or B10.A  T cells activated with syngeneic  splenic APC. Culture supernatants were harvested 24 h after  restimulation and IFN-γ, TNF-α,  and IL-4 were measured as  above. Data presented are means  and standard deviations of triplicate wells for each sample (n =  3). Similar results were obtained  in two additional experiments.
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Related In: Results  -  Collection

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Figure 4: Supernatant from B10.A T cells activated with B10.A APC for 2 h downregulates IFN-γ and TNF-α production by B10.BR Th1 cells when Ak-expressing L cell fibroblasts are used as APC. B10.BR (top bars) or B10.A (bottom bars) TCL 4 were activated with mMBP Ac1-16 and Ak-expressing L cell fibroblasts as APC for two consecutive restimulations in either normal medium or in 2-h supernatants from B10.BR or B10.A T cells activated with syngeneic splenic APC. Culture supernatants were harvested 24 h after restimulation and IFN-γ, TNF-α, and IL-4 were measured as above. Data presented are means and standard deviations of triplicate wells for each sample (n = 3). Similar results were obtained in two additional experiments.
Mentions: To begin to clarify the target of action of the B10.A-derived regulatory factor, B10.BR or B10.A T cells (TCL 4) were restimulated twice with mMBP Ac1-16 presented by nonprofessional APC (Ak-expressing L cells which do not produce splenic APC-derived cytokines), in the presence of 2-h supernatant from B10.A cultures. In either normal medium or in the 2-h B10.BR supernatant, B10.BR T cells produced high levels of IFN-γ and TNF-α, and B10.A T cells produced high levels of IL-4 with little or no TNF-α and IFN-γ. However, the levels of IFN-γ and TNF-α produced by B10.BR TCL were reduced in the presence of 2-h supernatant from B10.A cultures, similar to the effects seen when professional splenic APC were used (Fig. 4). This result indicates that B10.A-derived factor does not require the presence of splenic APC for its action and probably acts directly on the responding T cells.

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