Control of Th2-mediated inflammation by regulatory T cells

Abstract

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.

Figure 1

Foxp3 transcription is regulated by multiple transcription factors. Signals triggered by the ligation of TCR, CD28, TGF-β, and IL-2 result in the activation of the transcription factors cAMP responsive element binding protein (CREB), activating transcription factor (ATF), SP1, Ca+ calcineurin-dependent nuclear factor of activated T cells (NFAT), activator protein 1 (AP1), c-Rel, TGF-β-inducible early gene 1 (TIEG1), mothers against decapentaplegic homologue 3 (SMAD3), and signal transducer and activator of transcription 5 (STAT5). These transcription factors converge on the Foxp3 promoter to induce Foxp3 expression.

Figure 2

Foxp3+ Tregs regulate Th2-mediated inflammation and allergy. Natural Tregs (nTregs) inhibit priming and effector function of allergen-specific Th2 cells and prevent inflammation and allergy in non-atopic individuals. Induced Tregs (iTregs), which develop via conversion of naïve CD4 T cells into Foxp3+ Tregs during therapeutic exposure to allergens, can also function in this manner. TGF-β and retinoic acid (RA) may facilitate such conversion and provide protection against asthma and allergy.