CD25+CD4+ T cells and IgE-mediated disease in humans

University Of Virginia, Charlottesville VA

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Abstract

Allergic diseases such as asthma and atopic dermatitis (AD) are a major public health concern. Though a role for CD4+ T cells is well recognized in IgE-mediated disorders, the properties and function of these cells and the relationship to development of IgE responses and allergic inflammation remains enigmatic. A population of skin-homing CD4+ T cells which express high levels of CD25 (IL-2R<x chain) and the chemokine receptor, CCR4, is expanded in the blood of adult AD patients with high serum total IgE titers. Preliminary findings suggest that this population comprises a heterogeneous pool of pro-inflammatory activated effector T cells (CCR6+) and regulatory (Treg) cells. The principal goals of the proposed studies are to examine the link between discrete functional subsets of T cells within the CD25+CCR4+ pool and IgE responses and to define the mechanism whereby allergens promote expansion of these cells in the periphery. In Aim 1, the quotient of effector (CD27negCCR6+) and regulatory (CD27+Foxp3+) T cells within the CD25+CCR4+ subset will be compared between subjects with distinct IgE status and different IgE-mediated disorders. Cells will be stained for surface antigens and intracellular proteins and analyzed by 7-color flow cytometry. The anergic and suppressive capacity of CD27+ T cells will be assessed by T cell receptor triggering and reconstitution assays in order to define regulatory function. Dendritic cell/T cell co-cultures will be used to examine preferential induction of effector T cells by allergen within the CD25+CCR4+ compartment and to test whether GITR (glucocorticoid-induced TNFR-related protein) triggering modulates this effect. In Aim 2, combined cross-sectional and longitudinal studies in children (ages 0 to 17 years) with AD will be used to identify novel markers of disease progression and severity. Changes in discrete subsets of circulating CD25+CD4+ T cells associated with nascent and maturing IgE ab responses will be monitored by flow cytometry. The kinetics of IgE responses and production of pro-inflammatory cytokines/chemokines, including the CCR4-promoting chemokine, CCL17/TARC, will be assessed in parallel by multiplex cytometric bead assay. In Aim 3, cytokine/chemokine genes which are differentially expressed by CD25+CCR4+ T cells from asthmatic versus AD patients will be analyzed using microarray techniques. Antigens identified will be used as markers to monitor changes in circulating CD25+CCR4+ T cells isolated from asthmatic patients during an anti-lgE treatment regimen by flow cytometry. As an adjunct to these studies, the effect of experimental rhinovirus challenge on these cells and the relation to clinical disease will be assessed based on objective measures of lung function and inflammation. Studies in Aims 2 and 3 are pivotal to defining the relationship between discrete functional T cell subsets, IgE and allergic inflammatory processes. Public Health: Defining "pro-allergic" T cells and their link to IgE could provide new targets for therapy.