Functional Recognition Theory and Type 2 Immunity: Insights and Uncertainties

Abstract

Type 2 immunity plays an important role in host defense against helminths and toxins while driving allergic diseases. Despite progress in understanding the biology of type 2 immunity, the fundamental mechanisms regulating the type 2 immune module remain unclear. In contrast with structural recognition used by pattern recognition receptors, type 2 immunogens are sensed through their functional properties. Functional recognition theory has arisen as the paradigm for the initiation of type 2 immunity. However, the vast array of structurally unrelated type 2 immunogens makes it challenging to advance our understanding of type 2 immunity. In this article, we review functional recognition theory and organize type 2 immunogens into distinct classes based on how they fit into the concept of functional recognition. Lastly, we discuss areas of uncertainty in functional recognition theory with the goal of providing a framework to further define the logic of type 2 immunity in host protection and immunopathology.

FIGURE 1.. Functional recognition in the initiation of type 2 immunity at barrier surfaces.

Structurally unrelated type 2 immunogens, including those with undefined activities (question marks), are sensed at barrier surfaces by their shared ability to induce production of DAMPs and neuropeptides. DAMPs derived from epithelial cells and adventitial stromal cells, as well as other cell types, activate innate immune effectors such as mast cells and ILC2s. Neuropeptides such as neuromedin U promote the activation of ILC2s. The neuropeptide substance P enhances mast cell activation via MRGPRB2 and CD4⁺ Th2-skewing cDC2 trafficking via MRGPRA1, the latter promoting the differentiation of CD4⁺ Th2 and Tfh2 cells. Created with BioRender.com.