Regulation of T cell responses to allergens and environmental microbes

University Of Alabama At Birmingham, Birmingham AL

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Abstract

Summary. Asthma is a chronic lung disease that inflames/narrows the airways. Chronic allergic inflammation is primarily mediated by the aberrant activation/expansion of T-helper 2 (Th2) cells to airborne allergens. Interestingly, most people with Th2 asthma experience their first symptoms at a young age, suggesting that outcomes in adult asthma are determined in early childhood. In recent decades, incidence, morbidity, and mortality of pediatric allergic asthma and associated cost have been increasing worldwide, specifically among industrialized countries; and not due to the genetic background, but mainly because of the effect of environmental and lifestyle risk factors. The "hygiene hypothesis" proposes that the decreased exposure to dust containing high levels of bacterial endotoxin (LPS) and other microorganism-derived compounds at a very early age is one of the main drivers of the increasing incidence of asthma. However, no precise mechanism for this unique requirement for a high-LPS environment during infancy had been delineated. We have published that exposure to allergen induced allergen-specific Th2 cell responses; but exposure to allergen containing relatively low-doses of LPS prevented the initial priming of Th2 cells and development of subsequent Th2 cell- mediated inflammatory response in the airways of adult but not infant mice. These data show that adult and infant mice respond to LPS with different thresholds and, thus, relatively higher-doses of LPS are required to prevent Th2 cell responses and allergic inflammation in infant mice. Mechanistically, we found that unlike adult counterparts, infant conventional dendritic cells (cDCs) had impaired ability to suppress allergic-Th2 responses upon low-dose endotoxin sensitization. Importantly, our new data suggest that for the effective suppression of allergic Th2 cell activity, both the functional activation of cDCs, and the responsiveness of activated T cells are contingent on the coordinated actions of several cytokines (i.e., TNFα, IL-12, IL-18, IFNγ, and IL-6). Further, our data suggest that the first cells that sense LPS and produce cytokines to license the function of the cDCs are monocyte-derived dendritic cells (moDCs). Finally, our data show that the mother's milk-based diet conditions the differentiation and function of moDCs, which ultimately leads to a shift toward Th2 cell bias during infancy. Thus, we hypothesize that in response to low-dose LPS/allergen sensitization, moDCs initiate a cascade of cytokines, which ultimately mediate the suppression of Th2-driven allergic inflammation in adults. In infants, otherwise, this path is suppressed by the influence of the natural diet; rendering them more susceptible to allergy disease. In this proposal, we will test how specific cytokines modulate T helper cell program to allergens and how the infant diet and microbial exposure differentially affects this process. We believe the experiments in this proposal will significantly contribute to our understanding of how diet-environment interactions contribute to the development of allergic sensitization in children and ultimately will reveal new information about potential targets for prevention of asthma/allergies in children.