New paradigms in type 2 immunity

Abstract

Nearly half of the world's population harbors helminth infections or suffers from allergic disorders. A common feature of this population is the so-called "type 2 immune response," which confers protection against helminths, but also promotes pathologic responses associated with allergic inflammation. However, the mechanisms that initiate and control type 2 responses remain enigmatic. Recent advances have revealed a role for the innate immune system in orchestrating type 2 responses against a bewildering array of stimuli, from nanometer-sized allergens to 20-meter-long helminth parasites. Here, we review these advances and suggest that the human immune system has evolved multiple mechanisms of sensing such stimuli, from recognition of molecular patterns via innate immune receptors to detecting metabolic changes and tissue damage caused by these stimuli.

Fig. 1

Diversity of stimuli that induce type 2 immune responses. Such stimuli range from nanometersized allergens to 20-m-long helminthic parasites. Despite marked differences in size, shape, structure, and physical and chemical properties, all of these stimuli induce type 2 immune responses.

Fig. 2

Diverse mechanisms by which the innate immune system senses type 2–inducing stimuli. The host appears to have evolved multiple mechanisms to sense a bewildering array of stimuli that induce type 2 immune responses. Many pathogens and allergens can be sensed by pattern recognition receptors. In addition, proteolytic cleavage of host proteins by the protease activity of allergens, as well as tissue damage and metabolic changes caused by stimuli, may also be sensed by cells such as dendritic cells. Such diverse signals are decoded by dendritic cells to program type 2 immunity.

Fig. 3

Hierarchies of organization in the innate immune system. The complexity of the innate immune system in sensing stimuli and orchestrating type 2 immune responses can be conceptualized as occurring in different hierarchies of organization. The cell (that is, the dendritic cell) can be considered as the ground level; the innate receptors expressed by the cell and the signaling networks within the cell represent higher-resolution levels of the hierarchy. Conversely, cell-cell cooperation and the impact of the tissue microenvironment represent more global views of the hierarchy. This model offers a conceptual framework for therapeutic interventions to allergic inflammation. Thus, one might envision targeting the signaling level (for instance, by inhibiting ROS in DCs), the cellular level (for example, by inhibiting migration of cells such as DCs or basophils), or the cell-cell cooperation level (by inhibiting molecules such as TSLP, IL-25, and IL-33 that mediate cell interactions). RLR, RIG-I–like receptors; PI3K, phosphatidylinositol 3-kinase; NK-T, natural killer T cells.