Sentinels of the Type 2 Immune Response

Abstract

Type 2 immune responses have evolved to sense and respond to large, non-replicating infections or non-microbial noxious compounds in tissues. The development of these responses therefore depends upon highly coordinated and tightly regulated tissue-residing cellular sensors and responders. Multiple exposure to type 2 helper T cell (Th2)-inducing stimuli further enhances both the diversity and potency of the response. This review discusses advances in our understanding of the interacting cellular subsets that comprise both primary and secondary type 2 responses. Current knowledge regarding type 2 immune responses in the lung are initially presented and are then contrasted with what is known about the small intestine. The studies described portray an immune response that depends upon well-organized tissue structures, and suggest their modulation as a therapeutic strategy.

Figure 1. Type 2 sentinels of the primary and secondary immune response

The primary sentinels of type 2 stimuli in the lungs of SPF mice and humans include a diverse array of non-hematopoietic cells including specialized cells found within the airway epithelial layer, smooth muscle cells and neurons. Upon tissue perturbation these sensors release effector cytokines (IL-25, thymic stromal lymphopoietin (TSLP), IL-33, TNF-like ligand 1A (TL1A)), lipids (leukotrienes, prostaglandins), and neuropeptides (vasoactive intestinal peptide, neuromedin U) that converge upon the ILC2s which act as an innate sensing hub. Activated ILC2s are early producers of the canonical type 2 cytokines (IL-5, IL-13 and IL9) and may contribute to the adaptive immune response through either contact dependent or independent mechanisms. Inflammation leads to the development of tertiary lymphoid structures within the lung called inducible bronchus associated lymphoid tissue (iBALT) that support the entry and maintenance of activated and differentiated Th2 cells and B cells that further propagate the response (right panel). These adaptive immune cells can be maintained for long periods of time in the tissues where they lie in close proximity to each other and sites of antigen entry, therefore becoming major sentinels of a secondary type 2 stimulus that can rapidly clear a pathogen or cause pathology.