Inhibitory pattern recognition receptors

Abstract

Pathogen- and damage-associated molecular patterns are sensed by the immune system's pattern recognition receptors (PRRs) upon contact with a microbe or damaged tissue. In situations such as contact with commensals or during physiological cell death, the immune system should not respond to these patterns. Hence, immune responses need to be context dependent, but it is not clear how context for molecular pattern recognition is provided. We discuss inhibitory receptors as potential counterparts to activating pattern recognition receptors. We propose a group of inhibitory pattern recognition receptors (iPRRs) that recognize endogenous and microbial patterns associated with danger, homeostasis, or both. We propose that recognition of molecular patterns by iPRRs provides context, helps mediate tolerance to microbes, and helps balance responses to danger signals.

Figure 1.

The optimal threshold for activation is context dependent. The required threshold for activation of immune cells differs per location and depends on (1) the tolerance of the organ for immune pathology and (2) the tolerance to microbial exposure. Organs with a high regenerative capacity, such as the liver, are more able to deal with immunopathology than organs with low regenerative capacity, such as the heart or the brain. The gut and skin are constantly exposed to microbes, most of which are harmless or beneficial and should be tolerated. The eye can tolerate a certain amount of microbial exposure, and the cost of responding to a microbial stimulus will be high, so a high threshold will ensure the response occurs only when needed. In different organs, either tolerance for microbes or tolerance for immunopathology may be more important in determining the optimal threshold for activation.

Figure 2.

iPRRs and their endogenous and microbial ligands. The currently known group of iPRRs consist of CD300a/f, Siglecs 2, 3, and 5–11, CEACAM1, LILRB1 and LILRB3, TIGIT, poliovirus receptor (PVR), LAIR-1, and SIRL-1. The upper part of the figure displays endogenous ligands, and the bottom part displays the microbial ligands for iPRRs. For most receptors, both endogenous and exogenous ligands have been identified. Protein ligands are depicted as rectangles, lipids as circles, and carbohydrates as hexagons. All inhibitory receptors depicted are composed of Ig domains, and the number of Ig domains is schematically depicted for each receptor. In humans, most of these receptors are located in the chromosomal region 19q13, except CD300a/f (17q25) and TIGIT (3q13). *, LTA is a ligand for the mouse orthologue of the human LILRB3. PSM, phenol-soluble modulin; S100s, S100 proteins; SIA, sialic acid.

Figure 3.

The integration of activating and inhibitory signals determines the outcome of the immune response. When damage or a dangerous microbe should not be tolerated, DAMPs and PAMPs signal through activating PRRs to mount an immune response. However, when it is more beneficial for the host to tolerate damage or a harmless microbe, then the same DAMP or PAMP, or a different pattern, can concomitantly signal an iPRR to inhibit the immune response. The relative expression of PRRs and iPRRs and their respective ligands determine the strength of the resulting immune response.