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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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Peripheral T cells from mice injected with Ac1-11, Ac1-11[4A], or Ac1-11[4Y] hyperproliferate for the first 48 h after injection, but proliferate approximately as well as those from PBS-injected mice by day 6. The proliferative responses to Ac1-11, Ac1-11[4A], and Ac1-11[4Y] of cells from  PBS-injected mice (closed squares), Ac1-11–injected mice (open squares), Ac1-11[4A]–injected mice (closed circles), and Ac1-11[4Y]–injected mice (open circles) were determined in vitro as described in Materials and Methods.
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Figure 2: Peripheral T cells from mice injected with Ac1-11, Ac1-11[4A], or Ac1-11[4Y] hyperproliferate for the first 48 h after injection, but proliferate approximately as well as those from PBS-injected mice by day 6. The proliferative responses to Ac1-11, Ac1-11[4A], and Ac1-11[4Y] of cells from PBS-injected mice (closed squares), Ac1-11–injected mice (open squares), Ac1-11[4A]–injected mice (closed circles), and Ac1-11[4Y]–injected mice (open circles) were determined in vitro as described in Materials and Methods.

Mentions: The proliferative responses of T cells from lymph nodes from TCR trangenic mice treated with soluble PBS, Ac1-11, Ac1-11[4A], or Ac1-11[4Y] cultured with irradiated nontransgenic syngeneic splenocytes were enhanced after peptide treatment through day 2 (Fig. 2). In some experiments, proliferative responses increased with the affinity of the peptide for I-Au (data not shown). Similar results were found when splenocytes were cultured, except that cells from Ac1-11[4Y]–injected mice proliferated less well than or about equal to those from PBS-injected mice (data not shown). Approximately 60% of CD4+ T cells from lymph nodes from PBS-injected TCR transgenic mice fluxed calcium in response to Ac1-11 presented by nontransgenic syngeneic splenocytes; 24 h after injection, up to 90% of CD4+ T cells from lymph nodes from mice injected with either Ac1-11 or Ac1-11[4A] fluxed calcium, whereas only 20–30% of CD4+ T cells from mice injected with Ac111[4Y] fluxed calcium (data not shown). By 48 h, however, the number of cells from Ac1-11[4Y]–injected mice that fluxed calcium was equal to that of cells from PBSinjected mice, and both lymph node cells and splenocytes from Ac1-11–, Ac1-11[4A]–, and Ac1-11[4Y]–injected mice proliferated in an enhanced fashion (data not shown and Fig. 2). These results suggest that only Ac1-11[4Y] induces a transient hyporesponsiveness in the first 24 h and that this can be overcome by the presence of irradiated antigen presenting cells. By day 6, T cells from peptide-injected mice responded equally to those from PBS-injected mice, indicating that peptide-injection does not induce any longterm anergy (Fig. 2).


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)

Peripheral T cells from mice injected with Ac1-11, Ac1-11[4A], or Ac1-11[4Y] hyperproliferate for the first 48 h after injection, but proliferate approximately as well as those from PBS-injected mice by day 6. The proliferative responses to Ac1-11, Ac1-11[4A], and Ac1-11[4Y] of cells from  PBS-injected mice (closed squares), Ac1-11–injected mice (open squares), Ac1-11[4A]–injected mice (closed circles), and Ac1-11[4Y]–injected mice (open circles) were determined in vitro as described in Materials and Methods.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196136&req=5

Figure 2: Peripheral T cells from mice injected with Ac1-11, Ac1-11[4A], or Ac1-11[4Y] hyperproliferate for the first 48 h after injection, but proliferate approximately as well as those from PBS-injected mice by day 6. The proliferative responses to Ac1-11, Ac1-11[4A], and Ac1-11[4Y] of cells from PBS-injected mice (closed squares), Ac1-11–injected mice (open squares), Ac1-11[4A]–injected mice (closed circles), and Ac1-11[4Y]–injected mice (open circles) were determined in vitro as described in Materials and Methods.
Mentions: The proliferative responses of T cells from lymph nodes from TCR trangenic mice treated with soluble PBS, Ac1-11, Ac1-11[4A], or Ac1-11[4Y] cultured with irradiated nontransgenic syngeneic splenocytes were enhanced after peptide treatment through day 2 (Fig. 2). In some experiments, proliferative responses increased with the affinity of the peptide for I-Au (data not shown). Similar results were found when splenocytes were cultured, except that cells from Ac1-11[4Y]–injected mice proliferated less well than or about equal to those from PBS-injected mice (data not shown). Approximately 60% of CD4+ T cells from lymph nodes from PBS-injected TCR transgenic mice fluxed calcium in response to Ac1-11 presented by nontransgenic syngeneic splenocytes; 24 h after injection, up to 90% of CD4+ T cells from lymph nodes from mice injected with either Ac1-11 or Ac1-11[4A] fluxed calcium, whereas only 20–30% of CD4+ T cells from mice injected with Ac111[4Y] fluxed calcium (data not shown). By 48 h, however, the number of cells from Ac1-11[4Y]–injected mice that fluxed calcium was equal to that of cells from PBSinjected mice, and both lymph node cells and splenocytes from Ac1-11–, Ac1-11[4A]–, and Ac1-11[4Y]–injected mice proliferated in an enhanced fashion (data not shown and Fig. 2). These results suggest that only Ac1-11[4Y] induces a transient hyporesponsiveness in the first 24 h and that this can be overcome by the presence of irradiated antigen presenting cells. By day 6, T cells from peptide-injected mice responded equally to those from PBS-injected mice, indicating that peptide-injection does not induce any longterm anergy (Fig. 2).

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