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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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No net change in  the numbers of CD4+ T cells in  the periphery is observed after  peptide injection. The numbers  of CD4+ and CD8+ cells from  lymph nodes and spleen from  TCR transgenic mice injected  with PBS, Ac1-11, Ac1-11[4A],  or Ac1-11[4Y] are shown 1, 2,  and 6 d after a single administration of 2.4 mg of peptide. Black  bars represent the numbers of  CD4+ T cells in the spleen, dark  cross-hatched bars represent the  numbers of CD4+ T cells in  lymph nodes, shaded bars represent the numbers of CD8+ T  cells in the spleen, and light  cross-hatched bars represent the numbers of CD8+ T cells in the lymph nodes. Results are pooled from three experiments for days 1 and 6, and two experiments for day 2. In one experiment from day 3, CD4+ T cells had increased in number by 1.5–2-fold in peptide-injected mice (data not shown).
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Figure 3: No net change in the numbers of CD4+ T cells in the periphery is observed after peptide injection. The numbers of CD4+ and CD8+ cells from lymph nodes and spleen from TCR transgenic mice injected with PBS, Ac1-11, Ac1-11[4A], or Ac1-11[4Y] are shown 1, 2, and 6 d after a single administration of 2.4 mg of peptide. Black bars represent the numbers of CD4+ T cells in the spleen, dark cross-hatched bars represent the numbers of CD4+ T cells in lymph nodes, shaded bars represent the numbers of CD8+ T cells in the spleen, and light cross-hatched bars represent the numbers of CD8+ T cells in the lymph nodes. Results are pooled from three experiments for days 1 and 6, and two experiments for day 2. In one experiment from day 3, CD4+ T cells had increased in number by 1.5–2-fold in peptide-injected mice (data not shown).

Mentions: Despite the fact that T cells are hyperresponsive after peptide injection, the total number of CD4+ T cells increased only 1.5–2-fold over those of PBSinjected controls by day 2 and 3, and no significant net changes in the numbers of CD4+ T cells in the spleen or the lymph nodes were detected by day 6 (Fig. 3). When TCR transgenic mice were given four daily doses of 24 μg per dose, on average there was approximately a two- to threefold increase in the number of CD4+ T cells by day 6 (data not shown). Thus, significant numbers of responsive Ac1-11–specific T cells remain in the periphery, unlike CD4+ T cells in the 2B4, HNT-TCR, and DO11.10 TCR transgenic systems after peptide injection (15, 16, 35). Preliminary results using TCR transgenic mice on the B10.PL background indicate that each of the three peptides are able to induce CD4+ deletion, the degree of which correlates with the peptide affinity for the MHC (data not shown), suggesting that genetic background is important in determining the extent of peripheral deletion. In both the PL/J and B10.PL backgrounds, the numbers of CD8+ T cells, B cells, and macrophages do increase, however, by approximately twofold (data not shown). Presumably, CD8+ T cells are activated through cytokines produced by the CD4+ T cells, whereas B cells and macrophages are activated through interaction of the TCR with peptide/I-Au complex.


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)

No net change in  the numbers of CD4+ T cells in  the periphery is observed after  peptide injection. The numbers  of CD4+ and CD8+ cells from  lymph nodes and spleen from  TCR transgenic mice injected  with PBS, Ac1-11, Ac1-11[4A],  or Ac1-11[4Y] are shown 1, 2,  and 6 d after a single administration of 2.4 mg of peptide. Black  bars represent the numbers of  CD4+ T cells in the spleen, dark  cross-hatched bars represent the  numbers of CD4+ T cells in  lymph nodes, shaded bars represent the numbers of CD8+ T  cells in the spleen, and light  cross-hatched bars represent the numbers of CD8+ T cells in the lymph nodes. Results are pooled from three experiments for days 1 and 6, and two experiments for day 2. In one experiment from day 3, CD4+ T cells had increased in number by 1.5–2-fold in peptide-injected mice (data not shown).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: No net change in the numbers of CD4+ T cells in the periphery is observed after peptide injection. The numbers of CD4+ and CD8+ cells from lymph nodes and spleen from TCR transgenic mice injected with PBS, Ac1-11, Ac1-11[4A], or Ac1-11[4Y] are shown 1, 2, and 6 d after a single administration of 2.4 mg of peptide. Black bars represent the numbers of CD4+ T cells in the spleen, dark cross-hatched bars represent the numbers of CD4+ T cells in lymph nodes, shaded bars represent the numbers of CD8+ T cells in the spleen, and light cross-hatched bars represent the numbers of CD8+ T cells in the lymph nodes. Results are pooled from three experiments for days 1 and 6, and two experiments for day 2. In one experiment from day 3, CD4+ T cells had increased in number by 1.5–2-fold in peptide-injected mice (data not shown).
Mentions: Despite the fact that T cells are hyperresponsive after peptide injection, the total number of CD4+ T cells increased only 1.5–2-fold over those of PBSinjected controls by day 2 and 3, and no significant net changes in the numbers of CD4+ T cells in the spleen or the lymph nodes were detected by day 6 (Fig. 3). When TCR transgenic mice were given four daily doses of 24 μg per dose, on average there was approximately a two- to threefold increase in the number of CD4+ T cells by day 6 (data not shown). Thus, significant numbers of responsive Ac1-11–specific T cells remain in the periphery, unlike CD4+ T cells in the 2B4, HNT-TCR, and DO11.10 TCR transgenic systems after peptide injection (15, 16, 35). Preliminary results using TCR transgenic mice on the B10.PL background indicate that each of the three peptides are able to induce CD4+ deletion, the degree of which correlates with the peptide affinity for the MHC (data not shown), suggesting that genetic background is important in determining the extent of peripheral deletion. In both the PL/J and B10.PL backgrounds, the numbers of CD8+ T cells, B cells, and macrophages do increase, however, by approximately twofold (data not shown). Presumably, CD8+ T cells are activated through cytokines produced by the CD4+ T cells, whereas B cells and macrophages are activated through interaction of the TCR with peptide/I-Au complex.

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