Here, we investigated the targets of allergic T-cell responses in the TG system, independently of IgE reactivity, and with a specific focus on antigens that stimulate a Th2 response because of the role of this T-cell subset in mediating allergic reactions

Here, we investigated the targets of allergic T-cell responses in the TG system, independently of IgE reactivity, and with a specific focus on antigens that stimulate a Th2 response because of the role of this T-cell subset in mediating allergic reactions. Results Significant Fraction of TG-Reactive T Cells in Allergic Donors Does Not Target the Major IgE-Reactive Allergens. pollen transcriptome recognized 93 previously undescribed proteins for further study, 64 of which were not targeted by IgE. Predicted MHC binding peptides from your previoulsy undescribed TG proteins were screened for T-cell reactivity in peripheral blood mononuclear cells from allergic donors. Strong IL-5 production was detected in response to peptides from several of the previously undescribed proteins, most of which were not targeted by IgE. Responses against the dominant undescribed epitopes were associated with the memory T-cell subset and could even be detected directly ex lover vivo after Th2 cell enrichment. These findings demonstrate that a combined unbiased transcriptomic, proteomic, and immunomic approach identifies a greatly broadened repertoire of protein antigens targeted by T cells involved in allergy pathogenesis. The discovery of proteins that induce Th2 cells but are not IgE reactive may allow the development of safer immunotherapeutic strategies. Allergic diseases such as rhinitis and asthma present a significant burden to both patients and society as a whole (1). Recent studies have estimated that up to 20% of the population in the United States and Western Europe suffers from these diseases (2, 3). Despite this high incidence, existing therapy is mostly symptomatic, and immunotherapy treatments are successful in only a portion of patients and can be associated with significant security concerns (4). Consequently, much effort in allergy research has been devoted to the development of safer and more effective immunological treatments. Allergic respiratory diseases are associated with high levels of IgE antibodies to certain Mouse monoclonal to p53 allergenic proteins and elevated levels of eosinophils that Src Inhibitor 1 infiltrate the target tissue (5). Production of T helper 2 (Th2) cytokines [IL-4, -5, and -13 (6)] regulates these events because they are critical for the switch to IgE production by differentiating B cells and promote the influx of eosinophils and other inflammatory cells that contribute to airway pathology. Despite the importance of Th2 cells and their associated cytokines in the pathogenesis of allergic respiratory disease, studies of antigens considered as triggers of T-cell responses have so far been mostly limited to those known to bind IgE antibodies (7, 8) and induce IgE-mediated immediate hypersensitivity reactions (9). However, several clues suggest that T-cell and IgE reactivity might not exclusively be linked to each other. Studies conducted in mice have demonstrated the development of allergic airway hyperresponsiveness mediated by T cells in the absence of IgE (10, 11). Furthermore, data obtained from human studies have exhibited a lack of correlation between antigen-specific IgE levels and T-cell responses (12C16). The issue of whether T-cell acknowledgement is usually always necessarily linked to antibody recognition has broader significance in terms of the classic notion of linked acknowledgement of an antigen by both T helper cells and antigen-specific B cells. According to this notion, specific B cells internalize and process the antigen, leading to the presentation of antigen fragments bound by surface MHC class II molecules that can be recognized by specific T cells guaranteeing that this T cells deliver help to B cells specific for the same antigen (linked help). Although in some instances it has been shown that T cells can only or preferentially provide help to B cells specific for the same protein (17, 18), in other systems this restriction was not the case (19, 20). It was Src Inhibitor 1 found that two proteins that are present on the same particle could function together and that T cells specific for one protein could provide help for B cells specific for the second protein (20). Therefore, it may be possible that, as long as the antigen recognized by Src Inhibitor 1 T cells is usually in some physical association with the target of B-cell acknowledgement (as in the case of a small computer virus or a pollen particle), the integrity of the Src Inhibitor 1 antigenic bridge is usually preserved. In our previous study of T-cell responses against Timothy grass (TG) allergens (12), no correlation was detected between IgE levels and T-cell responses in TG pollen-allergic individuals. Furthermore, we found that one-third of the patients studied experienced no Th2 cell response against any of the known IgE-reactive proteins, despite strong responses against whole TG extract. Based on these observations, we hypothesized that TG pollen extract may contain previously undescribed T-cell Src Inhibitor 1 antigens in addition to the known IgE-inducing allergens. Here, we investigated the targets of allergic T-cell responses in the TG system, independently of IgE reactivity, and with a specific focus on antigens that stimulate.