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Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.

Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H, Kegel C, Disch R, Schmidt-Weber CB, Blaser K, Akdis CA - J. Exp. Med. (2004)

Bottom Line: Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4-secreting T cells in allergic individuals.Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-beta as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules.These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.

View Article: PubMed Central - PubMed

Affiliation: Swiss Institute of Allergy and Asthma Research, Obere Strasse 22, CH-7270 Davos. akdism@siaf.unizh.ch

ABSTRACT
The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4+ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-gamma-, interleukin (IL)-4-, and IL-10-producing allergen-specific CD4+ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1-like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4-secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-beta as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.

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Multiple suppressive mechanisms play a role in peripheral allergen tolerance. (A) Endogenous IL-10, TGF-β, or both as well as CTLA-4, PD-1, or both were neutralized in Der p 1–stimulated PBMCs of healthy individuals. [3H]Thymidine incorporation (TdR), IFN-γ, and IL-13 were determined at day 5. (B) Der p 1–specific proliferation of PBMCs from house dust mite allergic patients was suppressed by 10 times increased frequency of Der p 1–specific, IL-10–secreting T cells (IL-10+). The activity of IL-10, TGF-β, CTLA-4, and PD-1 were neutralized. [3H]Thymidine incorporation (TdR), IFN-γ, and IL-13 were determined at day 5. (control) Isotype control antibody. (A and B) Same results were obtained in four independent experiments (two Bet v1 and two Der p 1) all performed with freshly purified cells without in vitro expansion. Bet v 1 stimulation in birch pollen–allergic individuals gave similar results. All of the neutralization experiments were significantly different from the control and IL-10–secreting T cell–suppressed condition at 0.3 μM allergen doses. P < 0.001.
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fig6: Multiple suppressive mechanisms play a role in peripheral allergen tolerance. (A) Endogenous IL-10, TGF-β, or both as well as CTLA-4, PD-1, or both were neutralized in Der p 1–stimulated PBMCs of healthy individuals. [3H]Thymidine incorporation (TdR), IFN-γ, and IL-13 were determined at day 5. (B) Der p 1–specific proliferation of PBMCs from house dust mite allergic patients was suppressed by 10 times increased frequency of Der p 1–specific, IL-10–secreting T cells (IL-10+). The activity of IL-10, TGF-β, CTLA-4, and PD-1 were neutralized. [3H]Thymidine incorporation (TdR), IFN-γ, and IL-13 were determined at day 5. (control) Isotype control antibody. (A and B) Same results were obtained in four independent experiments (two Bet v1 and two Der p 1) all performed with freshly purified cells without in vitro expansion. Bet v 1 stimulation in birch pollen–allergic individuals gave similar results. All of the neutralization experiments were significantly different from the control and IL-10–secreting T cell–suppressed condition at 0.3 μM allergen doses. P < 0.001.

Mentions: Neutralization experiments revealed that all four suppressive mechanisms may play a role in suppression of allergen-specific Th2 cells. Der p 1– or Bet v 1–stimulated PBMCs of healthy individuals did not show any T cell proliferation. In both cases, neutralization of IL-10 and TGF-β activity significantly enhanced antigen-induced proliferation as well as IL-13 and IFN-γ production (Fig. 6 A). In addition, two other mechanisms apparently function in healthy immune response to allergens because neutralization of CTLA-4 or PD-1 significantly enhanced T cell proliferation and IFN-γ and IL-13 secretion in healthy individuals. In allergic individuals, Der p 1–induced T cell proliferation was significantly high in PBMCs of house dust mite allergic donors. A very clear suppression was achieved by increasing the frequency of Der p 1–specific, IL-10–secreting T cells. This suppression was partially inhibited by blocking of IL-10R, TGF-β, CTLA-4, or PD-1 (Fig. 6 B). In these experiments, IL-10R–blocking mAbs may block IL-10R on the APCs as well as on Tr1 cells; in addition, TGF-β secreted from both Tr1 cells and APCs can be neutralized by sTGF-βR. CTLA-4 and PD-1 are blocked particularly on the surface of Tr1 cells. These data demonstrate that IL-10, TGF-β, CTLA-4, and PD-1 cooperate in the suppression of immune response to allergens.


Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.

Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H, Kegel C, Disch R, Schmidt-Weber CB, Blaser K, Akdis CA - J. Exp. Med. (2004)

Multiple suppressive mechanisms play a role in peripheral allergen tolerance. (A) Endogenous IL-10, TGF-β, or both as well as CTLA-4, PD-1, or both were neutralized in Der p 1–stimulated PBMCs of healthy individuals. [3H]Thymidine incorporation (TdR), IFN-γ, and IL-13 were determined at day 5. (B) Der p 1–specific proliferation of PBMCs from house dust mite allergic patients was suppressed by 10 times increased frequency of Der p 1–specific, IL-10–secreting T cells (IL-10+). The activity of IL-10, TGF-β, CTLA-4, and PD-1 were neutralized. [3H]Thymidine incorporation (TdR), IFN-γ, and IL-13 were determined at day 5. (control) Isotype control antibody. (A and B) Same results were obtained in four independent experiments (two Bet v1 and two Der p 1) all performed with freshly purified cells without in vitro expansion. Bet v 1 stimulation in birch pollen–allergic individuals gave similar results. All of the neutralization experiments were significantly different from the control and IL-10–secreting T cell–suppressed condition at 0.3 μM allergen doses. P < 0.001.
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Related In: Results  -  Collection

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fig6: Multiple suppressive mechanisms play a role in peripheral allergen tolerance. (A) Endogenous IL-10, TGF-β, or both as well as CTLA-4, PD-1, or both were neutralized in Der p 1–stimulated PBMCs of healthy individuals. [3H]Thymidine incorporation (TdR), IFN-γ, and IL-13 were determined at day 5. (B) Der p 1–specific proliferation of PBMCs from house dust mite allergic patients was suppressed by 10 times increased frequency of Der p 1–specific, IL-10–secreting T cells (IL-10+). The activity of IL-10, TGF-β, CTLA-4, and PD-1 were neutralized. [3H]Thymidine incorporation (TdR), IFN-γ, and IL-13 were determined at day 5. (control) Isotype control antibody. (A and B) Same results were obtained in four independent experiments (two Bet v1 and two Der p 1) all performed with freshly purified cells without in vitro expansion. Bet v 1 stimulation in birch pollen–allergic individuals gave similar results. All of the neutralization experiments were significantly different from the control and IL-10–secreting T cell–suppressed condition at 0.3 μM allergen doses. P < 0.001.
Mentions: Neutralization experiments revealed that all four suppressive mechanisms may play a role in suppression of allergen-specific Th2 cells. Der p 1– or Bet v 1–stimulated PBMCs of healthy individuals did not show any T cell proliferation. In both cases, neutralization of IL-10 and TGF-β activity significantly enhanced antigen-induced proliferation as well as IL-13 and IFN-γ production (Fig. 6 A). In addition, two other mechanisms apparently function in healthy immune response to allergens because neutralization of CTLA-4 or PD-1 significantly enhanced T cell proliferation and IFN-γ and IL-13 secretion in healthy individuals. In allergic individuals, Der p 1–induced T cell proliferation was significantly high in PBMCs of house dust mite allergic donors. A very clear suppression was achieved by increasing the frequency of Der p 1–specific, IL-10–secreting T cells. This suppression was partially inhibited by blocking of IL-10R, TGF-β, CTLA-4, or PD-1 (Fig. 6 B). In these experiments, IL-10R–blocking mAbs may block IL-10R on the APCs as well as on Tr1 cells; in addition, TGF-β secreted from both Tr1 cells and APCs can be neutralized by sTGF-βR. CTLA-4 and PD-1 are blocked particularly on the surface of Tr1 cells. These data demonstrate that IL-10, TGF-β, CTLA-4, and PD-1 cooperate in the suppression of immune response to allergens.

Bottom Line: Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4-secreting T cells in allergic individuals.Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-beta as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules.These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.

View Article: PubMed Central - PubMed

Affiliation: Swiss Institute of Allergy and Asthma Research, Obere Strasse 22, CH-7270 Davos. akdism@siaf.unizh.ch

ABSTRACT
The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4+ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-gamma-, interleukin (IL)-4-, and IL-10-producing allergen-specific CD4+ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1-like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4-secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-beta as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.

Show MeSH
Related in: MedlinePlus