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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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Thymic architecture of MBP-specific TCR transgenic mice  and a normal nontransgenic littermate, as illustrated by ERTR5, an antibody that is specific for medullary epithelium. (A) Thymus from a MBPspecific TCR transgenic. (B) Thymus from a nontransgenic littermate.  Thymi were from the MBP-specific TCR transgenic line that has a CD4/ CD8 ratio of ∼5:1 and a less pronounced thymic defect than the line  with the higher CD4/CD8 ratio. Mice were (PL/J × B10.PL)F1. c, cortex; m, medulla.
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Figure 1: Thymic architecture of MBP-specific TCR transgenic mice and a normal nontransgenic littermate, as illustrated by ERTR5, an antibody that is specific for medullary epithelium. (A) Thymus from a MBPspecific TCR transgenic. (B) Thymus from a nontransgenic littermate. Thymi were from the MBP-specific TCR transgenic line that has a CD4/ CD8 ratio of ∼5:1 and a less pronounced thymic defect than the line with the higher CD4/CD8 ratio. Mice were (PL/J × B10.PL)F1. c, cortex; m, medulla.

Mentions: Two lines of transgenic mice were established. In one line, both the α and β transgenes were integrated onto the X chromosome. In this line, >90% of T cells from males expressed Vβ8.2, whereas only 50% of T cells from females express Vβ8.2, presumably due to random inactivation of the X chromosome on a cell by cell basis. In males, the CD4/CD8 ratio is increased by ∼15-fold over that of normal, whereas in females, the CD4/CD8 ratio is ∼1.5-fold over that of normal. In the second line, the transgenes were integrated onto an autosomal chromosome, and >90% of T cells from both males and females express Vβ8.2. The CD4/CD8 ratio in the second line is increased by fivefold over that of normal. In males of the first line and all mice of the second line, at least 60% of CD4+ T cells express the Ac1-11–specific αβ-TCR as judged by the number of CD4+ T cells that flux calcium in response to splenocytes presenting Ac1-11 (data not shown). Lymph node or spleen cells from either line when cultured in vitro with Ac1-11, Ac1-11[4A], or Ac1-11[4Y] spontaneously proliferate (data not shown). Routine hematoxylin and eosin staining of sections of the thymus from both lines of our TCR transgenic mice revealed that the thymi do not have a clearly defined cortex and medulla, an observation first noted in two other independent Ac1-11– specific TCR transgenic mice (33a). Interestingly, the thymus from the line with a higher CD4/CD8 ratio has a more severe defect than the line with a lower CD4/CD8 ratio. Specific staining of sections from thymi from the second MBP-specific TCR transgenic line that has a lower CD4/CD8 ratio shows that medullary epithelial cells are scattered throughout the thymus (Fig. 1). The cortex has a decreased size, while macrophage and dendritic cell populations appear normal (data not shown). To determine whether this defect was specific to these particular MBPspecific TCR transgenic mouse lines, we examined whether other class II–restricted TCR transgenic lines that have a high CD4/CD8 ratio have abnormal thymic architecture. All three different TCR transgenic lines examined so far, 2B4 (34) and 5C.C7 (35), both cytochrome c-specific and I-Ek– restricted, and DO11.10 (36), specific for ovalbumin peptide 323-339 and restricted to I-Ad, show a similar defect when examined by hematoxylin and eosin stains (data not shown and Table 1). These data suggest that a normal medullary and cortical epithelial architecture is disrupted by the increased numbers of single positive (SP) and/or decreased numbers of double positive (DP) cells found in these TCR transgenic mice.


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)

Thymic architecture of MBP-specific TCR transgenic mice  and a normal nontransgenic littermate, as illustrated by ERTR5, an antibody that is specific for medullary epithelium. (A) Thymus from a MBPspecific TCR transgenic. (B) Thymus from a nontransgenic littermate.  Thymi were from the MBP-specific TCR transgenic line that has a CD4/ CD8 ratio of ∼5:1 and a less pronounced thymic defect than the line  with the higher CD4/CD8 ratio. Mice were (PL/J × B10.PL)F1. c, cortex; m, medulla.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196136&req=5

Figure 1: Thymic architecture of MBP-specific TCR transgenic mice and a normal nontransgenic littermate, as illustrated by ERTR5, an antibody that is specific for medullary epithelium. (A) Thymus from a MBPspecific TCR transgenic. (B) Thymus from a nontransgenic littermate. Thymi were from the MBP-specific TCR transgenic line that has a CD4/ CD8 ratio of ∼5:1 and a less pronounced thymic defect than the line with the higher CD4/CD8 ratio. Mice were (PL/J × B10.PL)F1. c, cortex; m, medulla.
Mentions: Two lines of transgenic mice were established. In one line, both the α and β transgenes were integrated onto the X chromosome. In this line, >90% of T cells from males expressed Vβ8.2, whereas only 50% of T cells from females express Vβ8.2, presumably due to random inactivation of the X chromosome on a cell by cell basis. In males, the CD4/CD8 ratio is increased by ∼15-fold over that of normal, whereas in females, the CD4/CD8 ratio is ∼1.5-fold over that of normal. In the second line, the transgenes were integrated onto an autosomal chromosome, and >90% of T cells from both males and females express Vβ8.2. The CD4/CD8 ratio in the second line is increased by fivefold over that of normal. In males of the first line and all mice of the second line, at least 60% of CD4+ T cells express the Ac1-11–specific αβ-TCR as judged by the number of CD4+ T cells that flux calcium in response to splenocytes presenting Ac1-11 (data not shown). Lymph node or spleen cells from either line when cultured in vitro with Ac1-11, Ac1-11[4A], or Ac1-11[4Y] spontaneously proliferate (data not shown). Routine hematoxylin and eosin staining of sections of the thymus from both lines of our TCR transgenic mice revealed that the thymi do not have a clearly defined cortex and medulla, an observation first noted in two other independent Ac1-11– specific TCR transgenic mice (33a). Interestingly, the thymus from the line with a higher CD4/CD8 ratio has a more severe defect than the line with a lower CD4/CD8 ratio. Specific staining of sections from thymi from the second MBP-specific TCR transgenic line that has a lower CD4/CD8 ratio shows that medullary epithelial cells are scattered throughout the thymus (Fig. 1). The cortex has a decreased size, while macrophage and dendritic cell populations appear normal (data not shown). To determine whether this defect was specific to these particular MBPspecific TCR transgenic mouse lines, we examined whether other class II–restricted TCR transgenic lines that have a high CD4/CD8 ratio have abnormal thymic architecture. All three different TCR transgenic lines examined so far, 2B4 (34) and 5C.C7 (35), both cytochrome c-specific and I-Ek– restricted, and DO11.10 (36), specific for ovalbumin peptide 323-339 and restricted to I-Ad, show a similar defect when examined by hematoxylin and eosin stains (data not shown and Table 1). These data suggest that a normal medullary and cortical epithelial architecture is disrupted by the increased numbers of single positive (SP) and/or decreased numbers of double positive (DP) cells found in these TCR transgenic mice.

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