Mechanisms of DiseaseRelation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease
Introduction
Atopic allergic diseases such as asthma, rhinitis, and atopic dermatitis are characterised by presence of specific IgEs to allergens such as grass pollen, cat dander, or house dustmites.1 Activation of T helper (Th) 2 cells is thought to have a major role in allergic sensitisation, because such cells can mediate IgE synthesis via interleukin 4 and eosinophilic inflammation via interleukin 5, which, together with interleukin 13, contribute to airway hyper-responsiveness and other clinical features of allergic disease.1, 2 T-cell proliferation to allergen can be detected in primary cultures of peripheral blood mononuclear cells (PBMCs) from both atopic and non-atopic individuals. Such widespread priming is thought to be because many allergens implicated in asthma and rhinitis, such as cat dander and grass pollen, are widely distributed in the environment. Only PBMCs from atopic donors show increased production of Th2 cytokines interleukin 4, interleukin 5, and interleukin 13.3, 4, 5 We do not know why these individuals make a Th2-type T-cell response while other (non-atopic) people do not. One possibility is that regulatory mechanisms prevent IgE responses to allergens in non-atopic individuals. Potential mechanisms include suppression of Th2 responses by REGULATORY T CELLS.
Regulatory cd4+cd25+ t cells were characterised in mice as T cells that prevent development of organ-specific autoimmune disease in vivo and inhibit activation of CD4+CD25– T cells by polyclonal or antigenic stimulation in vitro.6, 7, 8 A similar population of suppressor CD4+CD25+ T cells has been described in human beings from both peripheral blood and thymus.9, 10, 11 CD25 is an imperfect marker for regulatory T cells, because it is also expressed by recently activated or memory T cells. Furthermore, other—possibly separate—regulatory T-cell populations have been described, including Th3 cells and T-regulatory-1 (Tr1) or interleukin 10-producing T cells.12, 13, 14 The suppressive phenotype of CD4+CD25+ T cells is associated with expression of the transcription factor FOXP3, which may, thus, be used as a marker for these regulatory T cells.
Balance between activation and suppression of T-cell responses can be crucial in determining outcome of many immune-mediated diseases. Naturally occurring human regulatory T cells could have a role in prevention of transplant rejection,9 but may also prevent control of tumours.15 Findings of studies suggest that human regulatory T cells can also suppress responses to recall antigens, including allergens.16, 17, 18
We aimed to investigate the relation between activity of regulatory T cells and disease in human beings. Furthermore, we looked at the mechanism of suppression of allergen-induced T-cell activation by human CD4+CD25+ T cells. We postulated that CD4+CD25+ T cells generally inhibit potentially pathogenic Th2esponses to allergens, and that this process is deficient or overcome in individuals with atopic allergic diseases.
Section snippets
Participants
Between November, 2001, and September, 2003, we recruited non-atopic and atopic volunteers by advertisement and from staff of the National Heart and Lung Institute, London, and patients with seasonal allergic rhinitis to grass pollen (hayfever) from the allergy clinic of the Royal Brompton Hospital, London, and by advertisement. All volunteers completed a standard questionnaire about allergic symptoms and, to establish presence or absence of atopy, had skin-prick tests to common aeroallergens
Results
We recruited nine non-atopic donors, 12 atopic allergic volunteers, and 11 allergen-exposed people with hayfever. Table 1 shows participants' characteristics.
We first compared PBMCs, CD4+CD25–, and CD4+CD25+ T cells from non-atopic donors in allergen-driven cultures. CD4+CD25+ T cells showed little or no proliferation to allergen stimulation. By contrast, culture of CD4+CD25– T cells with allergen showed substantially enhanced proliferation and production of interleukin 5 when compared with
Discussion
We have shown that suppression by CD4+CD25+ T cells relates to clinical manifestation of allergy, since inhibition of allergen-driven responses by cells from atopic donors was less than those from non-atopic individuals, and least of all by those isolated from patients with active allergic disease (hayfever).
Although atopic and non-atopic donors show proliferation of PBMCs to allergen in culture, these groups differ by production of Th2 cytokines, particularly interleukins 5 and 13.3, 4, 5 We
GLOSSARY
- atopy
- Tendency to make IgE to common environmental proteins such as house dustmite or grass-pollen allergens. Atopic individuals can develop atopic allergic diseases such as asthma, rhinitis, and atopic dermatitis.
- cd4+cd25+ t cells
- T lymphocytes are cells of the immune system that control immune responses by recognition of specific sequences from foreign (or self) molecules presented by MHCs on antigen-presenting cells such as dendritic cells or macrophages. CD4 is a marker of the helper T cell
References (29)
- et al.
IL-5 secretion by allergen-stimulated CD4+ T cells in primary culture: relationship to expression of allergic disease
J Allergy Clin Immunol
(1997) Regulatory T cells: key controllers of immunologic self-tolerance
Cell
(2000)- et al.
The role of suppressor T cells in regulation of immune responses
J Allergy Clin Immunol
(2002) - et al.
Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress Th1 and Th2 cytokine production
J Allergy Clin Immunol
(2003) - et al.
Relation between occurrence of type 1 diabetes and asthma
Lancet
(2001) - et al.
B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes
Immunity
(2000) - et al.
Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy
J Allergy Clin Immunol
(2003) Allergy and allergic diseases
N Engl J Med
(2001)- et al.
Two types of murine helper T cell clone: I—definition according to profiles of lymphokine activities and secreted proteins
J Immunol
(1986) - et al.
Inhalant allergen-specific T-cell reactivity is detectable in close to 100% of atopic and normal individuals: covert responses are unmasked by serum-free medium
Clin Exp Allergy
(1995)
Allergen-stimulated interleukin-4 and interferon-gamma production in primary culture: responses of subjects with allergic rhinitis and normal controls
Immunology
Regulatory T cells in the control of immune pathology
Nat Immunol
Human CD25+CD4+T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function
J Exp Med
Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood
J Exp Med
Cited by (666)
Engineering nanoparticle therapeutics for food allergy
2024, Journal of Allergy and Clinical ImmunologySingle-cell RNA sequencing identifies precise tolerogenic cellular and molecular pathways induced by depigmented-polymerized grass pollen allergen extract
2023, Journal of Allergy and Clinical ImmunologyAllergen immunotherapy for allergic airway diseases: Use lessons from the past to design a brighter future
2022, Pharmacology and TherapeuticsTh1-like Treg in vitiligo: An incompetent regulator in immune tolerance
2022, Journal of AutoimmunityIt is no skin off my nose: The relationship between the skin and allergic rhinitis
2021, Annals of Allergy, Asthma and Immunology