Control of Th2-Mediated Inflammation by Regulatory T Cells

Allergic diseases and asthma are caused by dysregulated Th2-type immune responses, which drive disease development in susceptible individuals. Immune tolerance to allergens prevents inflammatory symptoms in the respiratory mucosa and provides protection against inflammation in the airways. Increasing evidence indicates that Foxp3+ regulatory T cells (Tregs) play a critical role in immune tolerance and control Th2-biased responses. Tregs develop in the thymus from CD4⁺ T cells (natural Tregs) and also in the periphery by the conversion of naïve CD4⁺ T cells (induced Tregs). Increased susceptibility to allergy and airway inflammation is hypothesized to result from impaired development and function of Tregs. Thus, strategies to induce allergen-specific Tregs hold great promise for treatment and prevention of asthma.The incidence of chronic inflammatory lung diseases, such as asthma, has increased dramatically in recent years in industrialized countries. Asthma is characterized by airway hyperresponsiveness, chronic pulmonary eosinophilia, elevated serum IgE, excessive mucus production, and airway remodeling.¹ These symptoms are believed to result from interactions between environmental stimuli and a variety of genes influencing immune and respiratory function. In susceptible individuals, environmental stimuli induce immune dysfunction, which drives Th2 responses to otherwise harmless antigens. Although it is clear that Th2 responses drive pathological changes in asthma, the mechanisms that develop in vivo to prevent Th2-driven inflammation in nonallergic individuals are not clear.The identification of reciprocally inhibitory functions of Th1 and Th2 cells led to the concept that a defect in Th1-type immune responses resulted in deregulated Th2 responses and increased incidence of allergic diseases. Based on this concept, the hygiene hypothesis was proposed, which posits that decreased exposure to Th1-inducing infections, such as mycobacteria and viruses, leads to unconstrained development of Th2 responses and increased incidence of allergic diseases.^1,2 However, this simple explanation is insufficient to explain many experimental findings. First, Th1-responding cells are not always beneficial in allergic asthma and have been reported to contribute to and exacerbate this disease.^3,4 For example, adoptive transfer of Th1 cells resulted in enhanced airway eosinophilia and Th2 responses.⁵ Similarly, inhaled recombinant interferon-γ did not significantly alter clinical symptoms in humans.⁶ Second, epidemiological data suggest a parallel increase in Th2-mediated allergic diseases and Th1-mediated autoimmune diseases, such as Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis.⁷ These findings suggest that other regulatory mechanisms play a critical role in inhibiting the development of inappropriate Th2 (and Th1) responses.The respiratory mucosal surface is exposed to a vast quantity of environmental antigens, which challenge the immune system. Thus, the immune system must discriminate between, and appropriately respond to, both pathogenic and innocuous antigens. Under nonallergic circumstances, soluble proteins do not provoke a strong immune response, but instead induce a state of antigen-specific tolerance or hyporesponsiveness. T cell tolerance is achieved through central and peripheral mechanisms. Central tolerance encompasses deletion of T cells during negative selection, as well as selection of Tregs in the thymus. On the other hand, peripheral tolerance encompasses the mechanisms that lead to T cell tolerance to antigens; these include ignorance, deletion, anergy induction, and active suppression by CD4+Foxp3+ regulatory T cells (Tregs).There is growing evidence that Tregs play an important role in inhibiting Th2-mediated responses to allergens and maintaining immune tolerance. Studies in mouse models have shown that peripheral CD4⁺ T cell tolerance, induced by respiratory exposure to allergens, prevents the development of allergen-induced airway hyperresponsiveness.⁸ Likewise, we have reported that intravenous administration of soluble antigens results in antigen-specific anergy in Th2 cells and reduces airway inflammation.⁹ In this review we summarize current knowledge of Treg development and their role in the regulation of Th2-mediated allergic responses.