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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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Soluble peptide induces apoptosis in lymph nodes. Sections from brachial or inguinal lymph nodes from Ac1-11–specific TCR transgenic  mice removed 24 h after intravenous injection with (A) PBS, (B) 2.4 mg of Ac1-11, (C) 2.4 mg of Ac1-11[4A], and (D) 2.4 mg of Ac1-11[4Y]. Apoptotic cells were visualized using the TUNEL reaction as described in Materials and Methods section and appear as dark spots.
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Figure 4: Soluble peptide induces apoptosis in lymph nodes. Sections from brachial or inguinal lymph nodes from Ac1-11–specific TCR transgenic mice removed 24 h after intravenous injection with (A) PBS, (B) 2.4 mg of Ac1-11, (C) 2.4 mg of Ac1-11[4A], and (D) 2.4 mg of Ac1-11[4Y]. Apoptotic cells were visualized using the TUNEL reaction as described in Materials and Methods section and appear as dark spots.

Mentions: Despite the lack of significant reduction in the numbers of CD4+ T cells in TCR transgenic mice on the PL/J background, apoptotic cells are detected in lymph nodes 24 h after injection of peptide (Fig. 4). The amount of apoptosis correlates with the affinity of the peptide such that Ac1-11 induces the least amount of apoptosis, Ac1-11[4A] induces an intermediate level, and Ac1-11[4Y] induces the greatest degree of apoptosis. Thus, T cells are apparently dying off rapidly enough to counteract any increase due to proliferation. Activation-induced cell death (AICD) accompanied by cytokine production was detected at 500 μM Ac1-11, 100 μM Ac1-11[4A], and 20 μM Ac1-11[4Y] in purified CD4+ T cells cultured in vitro (data not shown). These data differ from those of Critchfield et al., who detected AICD of Ac1-11–specific T cells at 100 μM MBP (9). T cells from our MBP TCR transgenic mice may have a higher threshold for activation-induced apoptosis due to a lower level of TCR expression on these T cells compared with the level on T cells from those TCR transgenic mice studied by Critchfield et al. (9).


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)

Soluble peptide induces apoptosis in lymph nodes. Sections from brachial or inguinal lymph nodes from Ac1-11–specific TCR transgenic  mice removed 24 h after intravenous injection with (A) PBS, (B) 2.4 mg of Ac1-11, (C) 2.4 mg of Ac1-11[4A], and (D) 2.4 mg of Ac1-11[4Y]. Apoptotic cells were visualized using the TUNEL reaction as described in Materials and Methods section and appear as dark spots.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Soluble peptide induces apoptosis in lymph nodes. Sections from brachial or inguinal lymph nodes from Ac1-11–specific TCR transgenic mice removed 24 h after intravenous injection with (A) PBS, (B) 2.4 mg of Ac1-11, (C) 2.4 mg of Ac1-11[4A], and (D) 2.4 mg of Ac1-11[4Y]. Apoptotic cells were visualized using the TUNEL reaction as described in Materials and Methods section and appear as dark spots.
Mentions: Despite the lack of significant reduction in the numbers of CD4+ T cells in TCR transgenic mice on the PL/J background, apoptotic cells are detected in lymph nodes 24 h after injection of peptide (Fig. 4). The amount of apoptosis correlates with the affinity of the peptide such that Ac1-11 induces the least amount of apoptosis, Ac1-11[4A] induces an intermediate level, and Ac1-11[4Y] induces the greatest degree of apoptosis. Thus, T cells are apparently dying off rapidly enough to counteract any increase due to proliferation. Activation-induced cell death (AICD) accompanied by cytokine production was detected at 500 μM Ac1-11, 100 μM Ac1-11[4A], and 20 μM Ac1-11[4Y] in purified CD4+ T cells cultured in vitro (data not shown). These data differ from those of Critchfield et al., who detected AICD of Ac1-11–specific T cells at 100 μM MBP (9). T cells from our MBP TCR transgenic mice may have a higher threshold for activation-induced apoptosis due to a lower level of TCR expression on these T cells compared with the level on T cells from those TCR transgenic mice studied by Critchfield et al. (9).

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