Regulatory T cells in many flavors control asthma

Abstract

That regulatory T cells (Tregs) have a crucial role in controlling allergic diseases such as asthma is now undisputed. The cytokines most commonly implicated in Treg-mediated suppression of allergic asthma are transforming growth factor-beta (TGF-beta) and interleukin (IL)-10). In addition to naturally occurring Tregs, adaptive Tregs, induced in response to foreign antigens, have been shown in recent studies. The concept of inducible/adaptive Tregs (iTregs) has considerable significance in preventing asthma if generated early enough in life. This is because cytokines such as IL-4 and IL-6 inhibit Foxp3 induction in naive CD4+ T cells and therefore de novo generation of Tregs can be expected to be less efficient when it is concomitant with effector cell development in response to an allergen. However, if iTregs can be induced, the process of infectious tolerance would facilitate expansion of the iTreg pool as suggested in the recent literature. It is tempting to speculate that there is a window of opportunity in early life in the context of a relatively immature immune system that is permissive for the generation of iTregs specific to a spectrum of allergens that would regulate asthma for lifelong. The focus of this review is the relevance of nTregs and iTregs in controlling asthma from early life into adulthood, the mechanisms underlying Treg function, and the prospects for using our current concepts to harness the full potential of Tregs to limit disease development and progression.

Figure 1

Induced Tregs specific to allergens in early life may be the elixir of asthma-free life. As shown recently , the fetus is constantly exposed to non-inherited maternal antigens (NIMA) which traverse the placenta and trigger the development of Tregs in the fetal lymph nodes. Tregs constitute a high percentage of total lymphocytes in the fetal lymph nodes. This pool of Tregs aids in tempering fetal immune responses against maternal antigens. During or after pregnancy, transfer of antigen and TGF-β across the placenta or via breast milk induces antigen-specific Tregs ,. The immune system’s ability to induce antigen-specific Tregs in early life suggests a unique window of opportunity to administer allergen based vaccines to infants for the induction of protective allergen-specific Tregs.

Figure 2

Mucosal tolerance favors iTreg development in lung-draining lymph nodes that have free reign in tolerance but compete with nTregs during inflammation. LAP associated membrane-bound (mTGF-β) on iTregs acts via infectious tolerance to increase its pool size . mTGF-β induces Notch activation and upregulation of the downstream repressor Hes1 in naïve CD4+ T cells . Hes1 has been shown to stabilize Foxp3 expression in Tregs . The iTregs efficiently suppress effector cell development (shown is Th2) in antigen-tolerized animals –,. In allergen-sensitized animals, the cytokines IL-4 and IL-6 released during priming events suppress Treg induction ,,,. However, the same cytokines promote nTreg proliferation while inducing Th2 differentiation,, (Th17 cells are also induced by allergens). The Th2 cells and nTregs traffic to the tissue in recall response to inhaled allergen where they downmodulate costimulatory molecules on DCs ,(not shown). If priming occurs at a distant site (skin, spleen), IL-10-expressing Tregs are favored,,, which are recruited to the lung in response to allergen challenge to suppress effector T cell functions.