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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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Specificity and growth requirements of purified allergen-specific T cells. (A) Bet v 1–, Der p 1–, and Cor a 1–specific IL-4–, IFN-γ–, and IL-10–secreting T cells (one allergic and one healthy donor each; closed symbols, allergic donors; open symbols, healthy donors) were purified and in vitro expanded, and 5 × 105 cells were cocultured with 5 × 105 autologous irradiated PBMCs as an APC source in the presence of the same antigen. [3H]Thymidine incorporation (TdR) was determined after 5 d. *, P < 0.001. (B) Purified Bet v 1–specific and Der p 1–specific T cells did not show any proliferative response to different control antigens (two representative of six experiments are shown; mean ± SD of triplicate cultures). TT, tetanus toxoid; us, unstimulated. (C) Growth factor requirements of antigen-specific IL-10–secreting T cells. After purification, Bet v 1– or Der p 1–specific IL-10–secreting T cells were first expanded for 10 d in the presence of IL-2, washed, and cultured (5 × 104 cells) with 1-nM doses of different cytokines. [3H]Thymidine incorporation was determined after 3 d (mean ± SD of three independent experiments are shown).
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fig2: Specificity and growth requirements of purified allergen-specific T cells. (A) Bet v 1–, Der p 1–, and Cor a 1–specific IL-4–, IFN-γ–, and IL-10–secreting T cells (one allergic and one healthy donor each; closed symbols, allergic donors; open symbols, healthy donors) were purified and in vitro expanded, and 5 × 105 cells were cocultured with 5 × 105 autologous irradiated PBMCs as an APC source in the presence of the same antigen. [3H]Thymidine incorporation (TdR) was determined after 5 d. *, P < 0.001. (B) Purified Bet v 1–specific and Der p 1–specific T cells did not show any proliferative response to different control antigens (two representative of six experiments are shown; mean ± SD of triplicate cultures). TT, tetanus toxoid; us, unstimulated. (C) Growth factor requirements of antigen-specific IL-10–secreting T cells. After purification, Bet v 1– or Der p 1–specific IL-10–secreting T cells were first expanded for 10 d in the presence of IL-2, washed, and cultured (5 × 104 cells) with 1-nM doses of different cytokines. [3H]Thymidine incorporation was determined after 3 d (mean ± SD of three independent experiments are shown).

Mentions: The antigen specificity of purified cytokine-secreting T cells was studied by stimulation with the allergen that was originally used for stimulation before purification and several control antigens in the presence of autologous APCs. Consistently, IL-10–secreting T cells showed very little or no allergen-induced proliferation (Fig. 2 A). The proliferative response of allergen-specific IL-4– and IFN-γ–secreting T cells was significantly high compared with IL-10–secreting T cells. There was no difference between different allergens. T cells purified by certain antigen stimulation did not show any cross-reactivity against control antigens (Fig. 2 B). All three subsets purified by Bet v 1 stimulation responded to Bet v 1, but not to tetanus toxoid and Der p 1. Similarly, Der p 1–specific T cell subsets showed proliferative response to Der p 1, but not to tetanus toxoid and Bet v 1 as control antigens. Although they did not proliferate by antigen stimulation, IL-10–secreting T cells used IL-2, IL-4, IL-7, and IL-15 as growth factors and showed significant proliferation (Fig. 2 C). Together with the quantitative cytokine mRNA profiles of freshly purified cells, these data demonstrate that allergen-specific Tr1-, Th1-, and Th2-like cells can be purified from human peripheral blood.


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)

Specificity and growth requirements of purified allergen-specific T cells. (A) Bet v 1–, Der p 1–, and Cor a 1–specific IL-4–, IFN-γ–, and IL-10–secreting T cells (one allergic and one healthy donor each; closed symbols, allergic donors; open symbols, healthy donors) were purified and in vitro expanded, and 5 × 105 cells were cocultured with 5 × 105 autologous irradiated PBMCs as an APC source in the presence of the same antigen. [3H]Thymidine incorporation (TdR) was determined after 5 d. *, P < 0.001. (B) Purified Bet v 1–specific and Der p 1–specific T cells did not show any proliferative response to different control antigens (two representative of six experiments are shown; mean ± SD of triplicate cultures). TT, tetanus toxoid; us, unstimulated. (C) Growth factor requirements of antigen-specific IL-10–secreting T cells. After purification, Bet v 1– or Der p 1–specific IL-10–secreting T cells were first expanded for 10 d in the presence of IL-2, washed, and cultured (5 × 104 cells) with 1-nM doses of different cytokines. [3H]Thymidine incorporation was determined after 3 d (mean ± SD of three independent experiments are shown).
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Related In: Results  -  Collection

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fig2: Specificity and growth requirements of purified allergen-specific T cells. (A) Bet v 1–, Der p 1–, and Cor a 1–specific IL-4–, IFN-γ–, and IL-10–secreting T cells (one allergic and one healthy donor each; closed symbols, allergic donors; open symbols, healthy donors) were purified and in vitro expanded, and 5 × 105 cells were cocultured with 5 × 105 autologous irradiated PBMCs as an APC source in the presence of the same antigen. [3H]Thymidine incorporation (TdR) was determined after 5 d. *, P < 0.001. (B) Purified Bet v 1–specific and Der p 1–specific T cells did not show any proliferative response to different control antigens (two representative of six experiments are shown; mean ± SD of triplicate cultures). TT, tetanus toxoid; us, unstimulated. (C) Growth factor requirements of antigen-specific IL-10–secreting T cells. After purification, Bet v 1– or Der p 1–specific IL-10–secreting T cells were first expanded for 10 d in the presence of IL-2, washed, and cultured (5 × 104 cells) with 1-nM doses of different cytokines. [3H]Thymidine incorporation was determined after 3 d (mean ± SD of three independent experiments are shown).
Mentions: The antigen specificity of purified cytokine-secreting T cells was studied by stimulation with the allergen that was originally used for stimulation before purification and several control antigens in the presence of autologous APCs. Consistently, IL-10–secreting T cells showed very little or no allergen-induced proliferation (Fig. 2 A). The proliferative response of allergen-specific IL-4– and IFN-γ–secreting T cells was significantly high compared with IL-10–secreting T cells. There was no difference between different allergens. T cells purified by certain antigen stimulation did not show any cross-reactivity against control antigens (Fig. 2 B). All three subsets purified by Bet v 1 stimulation responded to Bet v 1, but not to tetanus toxoid and Der p 1. Similarly, Der p 1–specific T cell subsets showed proliferative response to Der p 1, but not to tetanus toxoid and Bet v 1 as control antigens. Although they did not proliferate by antigen stimulation, IL-10–secreting T cells used IL-2, IL-4, IL-7, and IL-15 as growth factors and showed significant proliferation (Fig. 2 C). Together with the quantitative cytokine mRNA profiles of freshly purified cells, these data demonstrate that allergen-specific Tr1-, Th1-, and Th2-like cells can be purified from human peripheral blood.

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