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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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Antigen-specific suppression by Tr1 cells. (A) Der p 1–specific and Bet v 1–specific IL-4–secreting and IL-10–secreting T cells were purified from healthy individuals. Their frequency was calculated in CD4+ T cells, and 2 × 105 PBMCs were immediately reconstituted by increasing their frequency by 10 times (IL-4–secreting T cells, 0.02–0.2%; IL-10–secreting T cells, 0.05–0.5%). Cells were stimulated with the respective antigens and PPD. (B) Der p 1–specific IL-4–secreting and IL-10–secreting T cells were purified and in vitro expanded by IL-2/IL-4 and IL-2/IL-15, respectively. 2 × 105 PBMCs were enriched with 1,000 Der p 1–specific IL-4– or IL-10–secreting T cells or their combinations in IL-4–secreting/IL-10–secreting T cell ratios 1,000/1,000 (1:1), 1,000/500 (2:1), 1,000:250 (4:1), and 1,000:125 (8:1). Cells were stimulated with 0.3 μM Der p 1 or 1 μg/ml PPD. Der p 1–specific, IL-10–secreting T cells added to PPD-stimulated PBMC cultures at indicated numbers did not show any suppression. (C) The same experimental design as in A was used, and cells were stimulated with both Der p 1 and Bet v 1 (0.3 μM each). (A–C) [3H]Thymidine incorporation was determined after 5 d. The same results were obtained in three other experiments. *, P < 0.001. (D) 105 PBMCs were stimulated with anti-CD3 in the presence of different amounts of IL-10–secreting and IL-4-secreting T cells. [3H]Thymidine incorporation was determined after 3 d. Data represent two different experiments. *, P < 0.01.
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fig4: Antigen-specific suppression by Tr1 cells. (A) Der p 1–specific and Bet v 1–specific IL-4–secreting and IL-10–secreting T cells were purified from healthy individuals. Their frequency was calculated in CD4+ T cells, and 2 × 105 PBMCs were immediately reconstituted by increasing their frequency by 10 times (IL-4–secreting T cells, 0.02–0.2%; IL-10–secreting T cells, 0.05–0.5%). Cells were stimulated with the respective antigens and PPD. (B) Der p 1–specific IL-4–secreting and IL-10–secreting T cells were purified and in vitro expanded by IL-2/IL-4 and IL-2/IL-15, respectively. 2 × 105 PBMCs were enriched with 1,000 Der p 1–specific IL-4– or IL-10–secreting T cells or their combinations in IL-4–secreting/IL-10–secreting T cell ratios 1,000/1,000 (1:1), 1,000/500 (2:1), 1,000:250 (4:1), and 1,000:125 (8:1). Cells were stimulated with 0.3 μM Der p 1 or 1 μg/ml PPD. Der p 1–specific, IL-10–secreting T cells added to PPD-stimulated PBMC cultures at indicated numbers did not show any suppression. (C) The same experimental design as in A was used, and cells were stimulated with both Der p 1 and Bet v 1 (0.3 μM each). (A–C) [3H]Thymidine incorporation was determined after 5 d. The same results were obtained in three other experiments. *, P < 0.001. (D) 105 PBMCs were stimulated with anti-CD3 in the presence of different amounts of IL-10–secreting and IL-4-secreting T cells. [3H]Thymidine incorporation was determined after 3 d. Data represent two different experiments. *, P < 0.01.

Mentions: As aforementioned, all three subsets of single allergen-specific T cells are present in both healthy and allergic individuals. Accordingly, their role on allergen-induced T cell proliferation and whether this is influenced by changing their ratios was investigated. We assayed the allergen-induced proliferation of IL-4– and IL-10–secreting T cells by adding those purified cells back into autologous PBMCs. First, the antigen-specific suppressor effect of IL-10–secreting T cells was analyzed (Fig. 4 A). Bet v 1– and Der p 1–specific IL-4– and IL-10–secreting T cells were separately purified from the same healthy individuals. Their frequency was increased up to 10 times higher than initial levels in PBMCs. PBMCs alone did not show allergen-induced T cell proliferation, which was achieved by increasing the numbers of allergen-specific IL-4–secreting T cells. Der p 1–specific IL-10–secreting T cells only suppressed Der p 1–stimulated, but not Bet v 1– or PPD-stimulated proliferation. Similarly, Bet v 1–specific IL-10–secreting T cells only suppressed Bet v 1–stimulated, but not Der p 1– or PPD-stimulated proliferation. There was no cross-suppression of Der p 1–specific IL-10–secreting cells on Bet v 1 stimulation and Bet v 1–specific IL-10–secreting T cells on Der p 1 stimulation, as well as both IL-10–secreting T cells on PPD stimulation.


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)

Antigen-specific suppression by Tr1 cells. (A) Der p 1–specific and Bet v 1–specific IL-4–secreting and IL-10–secreting T cells were purified from healthy individuals. Their frequency was calculated in CD4+ T cells, and 2 × 105 PBMCs were immediately reconstituted by increasing their frequency by 10 times (IL-4–secreting T cells, 0.02–0.2%; IL-10–secreting T cells, 0.05–0.5%). Cells were stimulated with the respective antigens and PPD. (B) Der p 1–specific IL-4–secreting and IL-10–secreting T cells were purified and in vitro expanded by IL-2/IL-4 and IL-2/IL-15, respectively. 2 × 105 PBMCs were enriched with 1,000 Der p 1–specific IL-4– or IL-10–secreting T cells or their combinations in IL-4–secreting/IL-10–secreting T cell ratios 1,000/1,000 (1:1), 1,000/500 (2:1), 1,000:250 (4:1), and 1,000:125 (8:1). Cells were stimulated with 0.3 μM Der p 1 or 1 μg/ml PPD. Der p 1–specific, IL-10–secreting T cells added to PPD-stimulated PBMC cultures at indicated numbers did not show any suppression. (C) The same experimental design as in A was used, and cells were stimulated with both Der p 1 and Bet v 1 (0.3 μM each). (A–C) [3H]Thymidine incorporation was determined after 5 d. The same results were obtained in three other experiments. *, P < 0.001. (D) 105 PBMCs were stimulated with anti-CD3 in the presence of different amounts of IL-10–secreting and IL-4-secreting T cells. [3H]Thymidine incorporation was determined after 3 d. Data represent two different experiments. *, P < 0.01.
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fig4: Antigen-specific suppression by Tr1 cells. (A) Der p 1–specific and Bet v 1–specific IL-4–secreting and IL-10–secreting T cells were purified from healthy individuals. Their frequency was calculated in CD4+ T cells, and 2 × 105 PBMCs were immediately reconstituted by increasing their frequency by 10 times (IL-4–secreting T cells, 0.02–0.2%; IL-10–secreting T cells, 0.05–0.5%). Cells were stimulated with the respective antigens and PPD. (B) Der p 1–specific IL-4–secreting and IL-10–secreting T cells were purified and in vitro expanded by IL-2/IL-4 and IL-2/IL-15, respectively. 2 × 105 PBMCs were enriched with 1,000 Der p 1–specific IL-4– or IL-10–secreting T cells or their combinations in IL-4–secreting/IL-10–secreting T cell ratios 1,000/1,000 (1:1), 1,000/500 (2:1), 1,000:250 (4:1), and 1,000:125 (8:1). Cells were stimulated with 0.3 μM Der p 1 or 1 μg/ml PPD. Der p 1–specific, IL-10–secreting T cells added to PPD-stimulated PBMC cultures at indicated numbers did not show any suppression. (C) The same experimental design as in A was used, and cells were stimulated with both Der p 1 and Bet v 1 (0.3 μM each). (A–C) [3H]Thymidine incorporation was determined after 5 d. The same results were obtained in three other experiments. *, P < 0.001. (D) 105 PBMCs were stimulated with anti-CD3 in the presence of different amounts of IL-10–secreting and IL-4-secreting T cells. [3H]Thymidine incorporation was determined after 3 d. Data represent two different experiments. *, P < 0.01.
Mentions: As aforementioned, all three subsets of single allergen-specific T cells are present in both healthy and allergic individuals. Accordingly, their role on allergen-induced T cell proliferation and whether this is influenced by changing their ratios was investigated. We assayed the allergen-induced proliferation of IL-4– and IL-10–secreting T cells by adding those purified cells back into autologous PBMCs. First, the antigen-specific suppressor effect of IL-10–secreting T cells was analyzed (Fig. 4 A). Bet v 1– and Der p 1–specific IL-4– and IL-10–secreting T cells were separately purified from the same healthy individuals. Their frequency was increased up to 10 times higher than initial levels in PBMCs. PBMCs alone did not show allergen-induced T cell proliferation, which was achieved by increasing the numbers of allergen-specific IL-4–secreting T cells. Der p 1–specific IL-10–secreting T cells only suppressed Der p 1–stimulated, but not Bet v 1– or PPD-stimulated proliferation. Similarly, Bet v 1–specific IL-10–secreting T cells only suppressed Bet v 1–stimulated, but not Der p 1– or PPD-stimulated proliferation. There was no cross-suppression of Der p 1–specific IL-10–secreting cells on Bet v 1 stimulation and Bet v 1–specific IL-10–secreting T cells on Der p 1 stimulation, as well as both IL-10–secreting T cells on PPD stimulation.

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