Persistent central memory phenotype of circulating Fel d 1 peptide/DRB1*0101 tetramer-binding CD4(+) T cells
Medical Research Council Human Immunology Unit, University of Oxford, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom. Journal of Allergy and Clinical Immunology
(Impact Factor: 11.48).
01/2007; 118(6):1350-6. DOI: 10.1016/j.jaci.2006.07.040
Although substantial evidence suggests that T cells are important in the pathogenesis of atopic dermatitis (AD), little is known of the differentiation status of CD4+ T cells specific for common environmental allergens.
To determine the frequency, differentiation phenotype, and function of circulating allergen-specific CD4+ T cells in adult individuals with severe persistent AD and controls.
Using tetrameric complexes of an HLA DRB1*0101 restricted epitope from Fel d 1, the major IgE-reactive component of cat dander, we studied ex vivo and cultured T-cell frequency and phenotype in individuals with AD and healthy controls. Cytokine secretion was measured by ex vivo and cultured IFN-gamma, IL-4, and IL-10 enzyme linked immuno-spot analysis.
Ex vivo Fel d 1-specific DRB1*0101-restricted CD4+ T cells express high levels of CCR7, CD62L, CD27, and CD28 and proportionately low levels of tissue-specific homing receptors and TH1 and TH2 cytokine production, placing the cells largely within the central memory subgroup.
Circulating Fel d 1-specific DRB1*0101-restricted CD4+ T cells maintain central memory capacity, consistent with a potential to contribute to persisting clinical atopic disease.
Persisting central memory characteristics of allergen-specific CD4+ T cells in individuals with AD may contribute to chronic disease.
Available from: Tuure Kinnunen
- "This result is in line with our previous estimations on lipocalin allergen-specific CD4+ T cells, analyzed with the same method , ,  or with peptide-HLA class II tetramers . Exploiting the latter methodology, other investigators have reported similar or higher frequencies for CD4+ T cells specific to the cat allergen Fel d 1 , the birch pollen allergen Bet v 1 ,  or the mite allergens Der p 1 and 2 . "
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ABSTRACT: Lipocalin allergens form a notable group of proteins, as they contain most of the significant respiratory allergens from mammals. The basis for the allergenic capacity of allergens in the lipocalin family, that is, the development of T-helper type 2 immunity against them, is still unresolved. As immunogenicity has been proposed to be a decisive feature of allergens, the purpose of this work was to examine human CD4+ T cell responses to the major dog allergen Can f 1 and to compare them with those to its human homologue, tear lipocalin (TL). For this, specific T cell lines were induced in vitro from the peripheral blood mononuclear cells of Can f 1-allergic and healthy dog dust-exposed subjects with peptides containing the immunodominant T cell epitopes of Can f 1 and the corresponding TL peptides. We found that the frequency of Can f 1 and TL-specific T cells in both subject groups was low and close to each other, the difference being about two-fold. Importantly, we found that the proliferative responses of both Can f 1 and TL-specific T cell lines from allergic subjects were stronger than those from healthy subjects, but that the strength of the responses within the subject groups did not differ between these two antigens. Moreover, the phenotype of the Can f 1 and TL-specific T cell lines, determined by cytokine production and expression of cell surface markers, resembled each other. The HLA system appeared to have a minimal role in explaining the allergenicity of Can f 1, as the allergic and healthy subjects' HLA background did not differ, and HLA binding was very similar between Can f 1 and TL peptides. Along with existing data on lipocalin allergens, we conclude that strong antigenicity is not decisive for the allergenicity of Can f 1.
Available from: Michael Tarzi
- "We present here the first detailed description of CD154+ T cells responding to birch allergen in non-atopic control subjects and birch pollinosis patients. Activated Th1, Th2 and Tr1-like lymphocytes were identified in varying proportions in allergic and non-allergic participants, with considerable overlap between the groups, supporting the mixed cytokine profile previously described for a number of allergens [8,9]. However, we demonstrate a novel relationship between the frequencies of these T cell subsets in birch tolerance, maintaining a low Th2: Th1 ratio and an appropriate frequency of IL-10+ T cells. "
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Allergic sensitisation has been ascribed to a dysregulated relationship between allergen-specific Th1, Th2 and regulatory T cells. We hypothesised that the relationship between these T cell subsets could be better defined using a short-term allergen stimulation system followed by direct analysis of CD154-positive T cells. Using peripheral blood samples from birch pollinosis patients and healthy non-atopic controls, we sought to explore the frequencies and phenotype of birch-stimulated CD154-positive T helper cells following ex vivo birch allergen stimulation.
Activated CD154-positive Th1, Th2 and Tr1-like cells, that co-expressed IFNγ, IL-4 and IL-10 respectively, were identified in both birch-allergic and non-allergic participants. We observed a close correlation between Th1, Th2 and Tr1-like cell frequency in non-allergic volunteers, such that the three parameters increased together to maintain a low Th2: Th1 ratio. The relationship between Th1, Th2 and Tr1-like responses was dysregulated in birch-allergic patients, with abrogation of the IL-10 response and a higher Th2: Th1 ratio. A close correlation was observed between Th2 cell frequency and the absolute concentration of birch-specific IgE within the birch-allergic group, and we confirmed previous reports of a more differentiated T cell phenotype in allergic subjects.
The findings demonstrate an important balance between IFNγ, IL-4 and IL-10 T cell responses to birch allergen in health, where Th2 responses to allergens were frequently observed, but apparently balanced by Th1 and regulatory responses. The detection of CD154 positive T cells after short-term antigen stimulation may be a useful method for the detection of T cell responses to allergens when cost, speed and convenience are priorities.
Available from: Belinda J Hales
- "Allergen-stimulated cells can also be tracked ex vivo by tetramer-binding cells. A study of CD4+ T cells from atopic dermatitis patients with IgE antibody to the cat allergen Fel d 1 used tetramer binding to show a similar result, with most of the T cells being within the central memory compartment . Their frequency was about 0.01% for cells from atopic dermatitis patients and about 0.002% for cells from nonallergic people. "
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ABSTRACT: This overview describes the nature of the immune responses induced by the inhalation of allergens. There is a dichotomy in that B cells have multiple mechanisms that limit the amount of immunoglobulin E (IgE) antibody production, whereas T-cell responses are large even in nonallergic subjects. With the possible exception of responses to cat allergen, however, T cells from nonallergic subjects have limited effect or function of helping IgG antibody, and in house-dust mite allergy, this declines with age. Regulation by interleukin 10 (IL-10)-producing cells and CD25+ T-regulatory cells has been proposed, but critically, there is limited evidence for this, and many studies show the highest IL-10 production by cells from allergic subjects. Recent studies have shown the importance of nonlymphoid chemokines thymic stromal lymphopoietin and IL-27, so studying responses in situ is critical. Most sources of allergens have 1 or 2 dominant allergens, and for house-dust mite, it has been shown that people have a predictable responsiveness to high-, mid- and poor-IgE-binding proteins regardless of the total size of their response. This allergen hierarchy can be used to design improved allergen preparations and to investigate how antiallergen responses are regulated.
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