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Induction of apoptosis and T helper 2 (Th2) responses correlates with peptide affinity for the major histocompatibility complex in self-reactive T cell receptor transgenic mice.

Pearson CI, van Ewijk W, McDevitt HO - J. Exp. Med. (1997)

Bottom Line: Concomitantly, T cells apoptose in the periphery, the degree of which correlates with the affinity of the peptide for the MHC.In addition, a shift in the T helper phenotype of the surviving T cells occurs such that the low affinity peptide, Ac1-11, induces primarily a Th1 response, whereas the highest affinity peptide, Ac1-11[4Y], induces primarily a Th2 type response.These data show that both the nature and the presumed number of the peptide-MHC complexes formed during specific peptide therapy affect both the degree of peripheral programmed cell death as well as the outcome of the T helper subset response in vivo, leading to amelioration of disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stanford University Medical Center, California 94305, USA.

ABSTRACT
Multiple sclerosis is an autoimmune disease thought to be mediated by CD4+ T helper cells (Th). Experimental autoimmune encephalomyelitis is a rodent model of multiple sclerosis and has been used extensively to explore a variety of immunotherapies using soluble protein or peptide antigens. The underlying mechanisms of such therapy have been attributed to induction of T cell anergy, a switch in Th1 to Th2 responses, or peripheral deletion of autoreactive T cells. In this study, we have developed transgenic mice expressing a T cell receptor (TCR) specific for the NH2-terminal peptide Ac1-11 of the autoantigen myelin basic protein to explore the mechanism of soluble peptide therapy. T cells from these mice are highly skewed toward the CD4 population and have an abnormal thymic architecture, a phenomenon found in other TCR transgenic mice that exhibit a highly skewed CD4/CD8 ratio. Soluble Ac1-11 or the analogues Ac 1-11 [4A] or Ac1-11[4Y] (which bind to the major histocompatibility complex [MHC] class II molecule I-Au with increasing affinities) given intravenously activates T cells, rendering cells hyperresponsive in vitro for at least two days after injection. Concomitantly, T cells apoptose in the periphery, the degree of which correlates with the affinity of the peptide for the MHC. In addition, a shift in the T helper phenotype of the surviving T cells occurs such that the low affinity peptide, Ac1-11, induces primarily a Th1 response, whereas the highest affinity peptide, Ac1-11[4Y], induces primarily a Th2 type response. These data show that both the nature and the presumed number of the peptide-MHC complexes formed during specific peptide therapy affect both the degree of peripheral programmed cell death as well as the outcome of the T helper subset response in vivo, leading to amelioration of disease.

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The effect of anti–B7-2 on the in vivo expression of B7-1 and B7-2 and the development of Th2 responses in vivo after injection of Ac111[4Y]. TCR transgenic mice were injected intraperitoneally with either PBS or 100 μg of anti–B7-2 antibody GL-1 on days −1 and 0. On day 0, mice  were injected intravenously with either PBS or 2.4 mg of Ac1-11[4Y], and mice were killed on day 1. (A) The expression of B7-1 and B7-2 on B cells  and macrophages was determined as described in Materials and Methods. Solid lines, expression of B7-1 or B7-2 on cells from mice injected intravenously with PBS; dashed lines, expression on cells from mice injected with Ac1-11[4Y]. B7-1 was upregulated on macrophages from Ac1-11[4Y]– injected mice treated intraperitoneally with either PBS or anti–B7-2, while B7-2 was upregulated on B cells from Ac1-11[4Y]–injected mice given PBS  intraperitoneally, but not on cells from Ac1-11[4Y]–injected mice given anti–B7-2 intraperitoneally. (B). The cytokine profile of splenocytes in response  to 10 μM Ac1-11, Ac1-11[4A], or Ac1-11[4Y] was determined by ELISA as described. Black bars, cytokine response to Ac1-11 in secondary challenge;  shaded bars, cytokine response to Ac1-11[4A] in secondary challenge; cross-hatched bars, cytokine response to Ac1-11[4Y] in secondary challenge. IL-2  production was similar between mice given PBS or Ac1-11[4Y] intravenously, regardless of antibody treatment. IFN-γ production was increased approximately twofold in mice given both Ac1-11[4Y] and anti–B7-2 over that of cells from mice given only Ac1-11[4Y], while IL-4 and IL-10 production by  cells from mice given both Ac1-11[4Y] and anti–B7-2 was reduced by about two- to fourfold relative to production by cells from mice given Ac111[4Y] only.
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Figure 9: The effect of anti–B7-2 on the in vivo expression of B7-1 and B7-2 and the development of Th2 responses in vivo after injection of Ac111[4Y]. TCR transgenic mice were injected intraperitoneally with either PBS or 100 μg of anti–B7-2 antibody GL-1 on days −1 and 0. On day 0, mice were injected intravenously with either PBS or 2.4 mg of Ac1-11[4Y], and mice were killed on day 1. (A) The expression of B7-1 and B7-2 on B cells and macrophages was determined as described in Materials and Methods. Solid lines, expression of B7-1 or B7-2 on cells from mice injected intravenously with PBS; dashed lines, expression on cells from mice injected with Ac1-11[4Y]. B7-1 was upregulated on macrophages from Ac1-11[4Y]– injected mice treated intraperitoneally with either PBS or anti–B7-2, while B7-2 was upregulated on B cells from Ac1-11[4Y]–injected mice given PBS intraperitoneally, but not on cells from Ac1-11[4Y]–injected mice given anti–B7-2 intraperitoneally. (B). The cytokine profile of splenocytes in response to 10 μM Ac1-11, Ac1-11[4A], or Ac1-11[4Y] was determined by ELISA as described. Black bars, cytokine response to Ac1-11 in secondary challenge; shaded bars, cytokine response to Ac1-11[4A] in secondary challenge; cross-hatched bars, cytokine response to Ac1-11[4Y] in secondary challenge. IL-2 production was similar between mice given PBS or Ac1-11[4Y] intravenously, regardless of antibody treatment. IFN-γ production was increased approximately twofold in mice given both Ac1-11[4Y] and anti–B7-2 over that of cells from mice given only Ac1-11[4Y], while IL-4 and IL-10 production by cells from mice given both Ac1-11[4Y] and anti–B7-2 was reduced by about two- to fourfold relative to production by cells from mice given Ac111[4Y] only.

Mentions: Previous studies have indicated that co-stimulatory molecules influence T helper subset differentiation (see references 46 and 47). To test whether blocking upregulation of B7-2 on B cells would downregulate Th2 differentiation observed after Ac1-11[4Y] administration in vivo, 100 μg of anti–B7-2 antibody was given on day −1, and both antibody and 2.4 mg of Ac1-11[4Y] were given on day 0. 1 d after peptide administration, B7-1 was upregulated on macrophages, but not on B cells in both PBS- and anti–B7-2–treated mice given Ac1-11[4Y]. B7-2, in contrast, was upregulated on B cells in mice given Ac1-11[4Y] only, but not in mice given both Ac1-11[4Y] and anti–B7-2 antibody (Fig. 9 A). IL-2 production by splenocytes from Ac1-11[4Y]–treated mice having either no treatment or anti–B7-2 did not show any significant differences. In contrast, IFN-γ production by cells from anti– B7-2– and Ac1-11[4Y]–treated mice increased by approximately twofold, while IL-4 and IL-10 production decreased two- to fourfold relative to that by cells from Ac1-11[4Y]– treated mice (Fig. 9 B).


Induction of apoptosis and T helper 2 (Th2) responses correlates with peptide affinity for the major histocompatibility complex in self-reactive T cell receptor transgenic mice.

Pearson CI, van Ewijk W, McDevitt HO - J. Exp. Med. (1997)

The effect of anti–B7-2 on the in vivo expression of B7-1 and B7-2 and the development of Th2 responses in vivo after injection of Ac111[4Y]. TCR transgenic mice were injected intraperitoneally with either PBS or 100 μg of anti–B7-2 antibody GL-1 on days −1 and 0. On day 0, mice  were injected intravenously with either PBS or 2.4 mg of Ac1-11[4Y], and mice were killed on day 1. (A) The expression of B7-1 and B7-2 on B cells  and macrophages was determined as described in Materials and Methods. Solid lines, expression of B7-1 or B7-2 on cells from mice injected intravenously with PBS; dashed lines, expression on cells from mice injected with Ac1-11[4Y]. B7-1 was upregulated on macrophages from Ac1-11[4Y]– injected mice treated intraperitoneally with either PBS or anti–B7-2, while B7-2 was upregulated on B cells from Ac1-11[4Y]–injected mice given PBS  intraperitoneally, but not on cells from Ac1-11[4Y]–injected mice given anti–B7-2 intraperitoneally. (B). The cytokine profile of splenocytes in response  to 10 μM Ac1-11, Ac1-11[4A], or Ac1-11[4Y] was determined by ELISA as described. Black bars, cytokine response to Ac1-11 in secondary challenge;  shaded bars, cytokine response to Ac1-11[4A] in secondary challenge; cross-hatched bars, cytokine response to Ac1-11[4Y] in secondary challenge. IL-2  production was similar between mice given PBS or Ac1-11[4Y] intravenously, regardless of antibody treatment. IFN-γ production was increased approximately twofold in mice given both Ac1-11[4Y] and anti–B7-2 over that of cells from mice given only Ac1-11[4Y], while IL-4 and IL-10 production by  cells from mice given both Ac1-11[4Y] and anti–B7-2 was reduced by about two- to fourfold relative to production by cells from mice given Ac111[4Y] only.
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Figure 9: The effect of anti–B7-2 on the in vivo expression of B7-1 and B7-2 and the development of Th2 responses in vivo after injection of Ac111[4Y]. TCR transgenic mice were injected intraperitoneally with either PBS or 100 μg of anti–B7-2 antibody GL-1 on days −1 and 0. On day 0, mice were injected intravenously with either PBS or 2.4 mg of Ac1-11[4Y], and mice were killed on day 1. (A) The expression of B7-1 and B7-2 on B cells and macrophages was determined as described in Materials and Methods. Solid lines, expression of B7-1 or B7-2 on cells from mice injected intravenously with PBS; dashed lines, expression on cells from mice injected with Ac1-11[4Y]. B7-1 was upregulated on macrophages from Ac1-11[4Y]– injected mice treated intraperitoneally with either PBS or anti–B7-2, while B7-2 was upregulated on B cells from Ac1-11[4Y]–injected mice given PBS intraperitoneally, but not on cells from Ac1-11[4Y]–injected mice given anti–B7-2 intraperitoneally. (B). The cytokine profile of splenocytes in response to 10 μM Ac1-11, Ac1-11[4A], or Ac1-11[4Y] was determined by ELISA as described. Black bars, cytokine response to Ac1-11 in secondary challenge; shaded bars, cytokine response to Ac1-11[4A] in secondary challenge; cross-hatched bars, cytokine response to Ac1-11[4Y] in secondary challenge. IL-2 production was similar between mice given PBS or Ac1-11[4Y] intravenously, regardless of antibody treatment. IFN-γ production was increased approximately twofold in mice given both Ac1-11[4Y] and anti–B7-2 over that of cells from mice given only Ac1-11[4Y], while IL-4 and IL-10 production by cells from mice given both Ac1-11[4Y] and anti–B7-2 was reduced by about two- to fourfold relative to production by cells from mice given Ac111[4Y] only.
Mentions: Previous studies have indicated that co-stimulatory molecules influence T helper subset differentiation (see references 46 and 47). To test whether blocking upregulation of B7-2 on B cells would downregulate Th2 differentiation observed after Ac1-11[4Y] administration in vivo, 100 μg of anti–B7-2 antibody was given on day −1, and both antibody and 2.4 mg of Ac1-11[4Y] were given on day 0. 1 d after peptide administration, B7-1 was upregulated on macrophages, but not on B cells in both PBS- and anti–B7-2–treated mice given Ac1-11[4Y]. B7-2, in contrast, was upregulated on B cells in mice given Ac1-11[4Y] only, but not in mice given both Ac1-11[4Y] and anti–B7-2 antibody (Fig. 9 A). IL-2 production by splenocytes from Ac1-11[4Y]–treated mice having either no treatment or anti–B7-2 did not show any significant differences. In contrast, IFN-γ production by cells from anti– B7-2– and Ac1-11[4Y]–treated mice increased by approximately twofold, while IL-4 and IL-10 production decreased two- to fourfold relative to that by cells from Ac1-11[4Y]– treated mice (Fig. 9 B).

Bottom Line: Concomitantly, T cells apoptose in the periphery, the degree of which correlates with the affinity of the peptide for the MHC.In addition, a shift in the T helper phenotype of the surviving T cells occurs such that the low affinity peptide, Ac1-11, induces primarily a Th1 response, whereas the highest affinity peptide, Ac1-11[4Y], induces primarily a Th2 type response.These data show that both the nature and the presumed number of the peptide-MHC complexes formed during specific peptide therapy affect both the degree of peripheral programmed cell death as well as the outcome of the T helper subset response in vivo, leading to amelioration of disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stanford University Medical Center, California 94305, USA.

ABSTRACT
Multiple sclerosis is an autoimmune disease thought to be mediated by CD4+ T helper cells (Th). Experimental autoimmune encephalomyelitis is a rodent model of multiple sclerosis and has been used extensively to explore a variety of immunotherapies using soluble protein or peptide antigens. The underlying mechanisms of such therapy have been attributed to induction of T cell anergy, a switch in Th1 to Th2 responses, or peripheral deletion of autoreactive T cells. In this study, we have developed transgenic mice expressing a T cell receptor (TCR) specific for the NH2-terminal peptide Ac1-11 of the autoantigen myelin basic protein to explore the mechanism of soluble peptide therapy. T cells from these mice are highly skewed toward the CD4 population and have an abnormal thymic architecture, a phenomenon found in other TCR transgenic mice that exhibit a highly skewed CD4/CD8 ratio. Soluble Ac1-11 or the analogues Ac 1-11 [4A] or Ac1-11[4Y] (which bind to the major histocompatibility complex [MHC] class II molecule I-Au with increasing affinities) given intravenously activates T cells, rendering cells hyperresponsive in vitro for at least two days after injection. Concomitantly, T cells apoptose in the periphery, the degree of which correlates with the affinity of the peptide for the MHC. In addition, a shift in the T helper phenotype of the surviving T cells occurs such that the low affinity peptide, Ac1-11, induces primarily a Th1 response, whereas the highest affinity peptide, Ac1-11[4Y], induces primarily a Th2 type response. These data show that both the nature and the presumed number of the peptide-MHC complexes formed during specific peptide therapy affect both the degree of peripheral programmed cell death as well as the outcome of the T helper subset response in vivo, leading to amelioration of disease.

Show MeSH
Related in: MedlinePlus