Reversal of Allergic Airway Hyperreactivity after Long-term Allergen Challenge Depends on γδ T Cells

Abstract

Long-term allergen exposure can attenuate inflammation and revert airway hyperreactivity to normal responsiveness. A model of such reversal was established in which airway hyperreactivity and inflammation in ovalbumin-sensitized and challenged mice were decreased after multiple daily airway challenges. This change in responsiveness and inflammation was associated with a transition from a helper T cell Type 2 to a helper T cell Type 1 cytokine-biased profile in bronchoalveolar lavage fluid. Cell transfer from long-term exposed mice into hyperreactive mice also restored normal airway responsiveness, establishing the mechanism underlying the reversal of the hyperreactivity as active suppression, but did not affect eosinophilic airway inflammation. Conversely, airway hyperreactivity, suppressed as a result of long-term allergen exposure, could be reestablished by depleting gammadelta T cells, in particular Vgamma4+ cells. Antigen-specific tolerance of alphabeta T cells or suppression by non-gammadelta T cells did not play a role in the reversal to normal airway responsiveness and gammadelta T cells did not play a role in the regulation of the allergic inflammatory response. These findings show that normal responsiveness in previously hyperreactive mice, achieved after long-term allergen challenge, is based on several, apparently independent regulatory mechanisms. One of these, focused on airway responsiveness, involves active suppression and requires gammadelta T cells.

Requirement of L-selectin for γδ T lymphocyte activation and migration during allergic pleurisy: Co-relation with eosinophil accumulation

“…OVA challenge induces γδ T lymphocyte accumulation in pleural cavities of sensitized mice through a mechanism that relies on T cell migration induced by CCR2/CCL2 pathway, which starts at 12 h, peaks at 48 h and returns to basal levels 5 days after stimulation [32]. Indeed, γδ T lymphocytes are shown to accumulate in airways of allergic human patients and experimental animals submitted to antigenic challenge [7,8,[33][34][35], as well as to modulate several features of allergic responses, including eosinophil influx into inflamed tissue [6][7][8][9]. Our results show that i.t.…”

“…A few reports show that, in animal models and in allergic subjects, γδ T cells that accumulate in the inflammatory site contribute to eosinophil infiltration [6][7][8][9]. These cells undertake pro-inflammatory functions and induce immunoglobulin E synthesis via the regulation of IL-5 and IL-4 production, as demonstrated by means of the use of knockout mice or α-γδ antibody depletion [6][7][8][9].…”

“…These cells undertake pro-inflammatory functions and induce immunoglobulin E synthesis via the regulation of IL-5 and IL-4 production, as demonstrated by means of the use of knockout mice or α-γδ antibody depletion [6][7][8][9]. In these models of lung allergic inflammation, whether γδ T cells display pro-or antiinflammatory profiles seems to be determined by the γδ T cell subset involved in inflammatory response as well as by its tissue distribution [10,11].…”

Regulation of Mucous Cell Metaplasia in Bronchial Asthma

“…In rodents, chronic exposure to an allergen initially induces inflammation, which decreases over time [58,59] while in humans with allergic asthma, inflammation persists and is chronic during their lifetime [60]. This transition from antigen sensitization to immunological tolerance is accompanied by a shift in the lymphocyte content in the lung tissue and bronchial lavage fluid (BALF) [61,58]. Antigen-specific regulatory T cells are believed to produce IL-10 transiently and inhibit the asthma phenotype during the development of tolerance [62,63].…”

Insights into the Pathogenesis of Asthma Utilizing Murine Models

“…To create a chronic model with features of airway remodeling, different approaches have been tried, mainly by sustaining airway challenges over weeks to months following the initial acute response. One of the problems encountered in mice with repeated challenges over a prolonged period of time is that the phenotype, AHR and airway inflammation, become attenuated [40, 140, 141]. This phenomenon, however, seems to be closely related to continuous allergen exposure, which leads to a form of ‘tolerance’.…”