Constitutive immune mechanisms: mediators of host defence and immune regulation

Abstract

The immune system enables organisms to combat infections and to eliminate endogenous challenges. Immune responses can be evoked through diverse inducible pathways. However, various constitutive mechanisms are also required for immunocompetence. The inducible responses of pattern recognition receptors of the innate immune system and antigen-specific receptors of the adaptive immune system are highly effective, but they also have the potential to cause extensive immunopathology and tissue damage, as seen in many infectious and autoinflammatory diseases. By contrast, constitutive innate immune mechanisms, including restriction factors, basal autophagy and proteasomal degradation, tend to limit immune responses, with loss-of-function mutations in these pathways leading to inflammation. Although they function through a broad and heterogeneous set of mechanisms, the constitutive immune responses all function as early barriers to infection and aim to minimize any disruption of homeostasis. Supported by recent human and mouse data, in this Review we compare and contrast the inducible and constitutive mechanisms of immunosurveillance.

Fig. 1. Constitutive innate immune responses versus inducible immune responses.

Illustration of how constitutive and inducible immune responses vary over time during the course of a generalized infection, and their impact on host defence, energy consumption and host fitness. In the case of a sterilizing and resolving immune response, the additional energy consumption required by the inducible immune response is balanced by the re-establishment of homeostasis. By contrast, in the case of an immunopathological response, the energy that is consumed to mount an inducible response does not benefit the host and instead leads to tissue damage and disruption of homeostasis.

Fig. 2. Constitutive innate immune responses negatively regulate inducible immune responses.

a | Constitutive innate immune mechanisms eliminate pathogens during the initial stages of an infection, which prevents the accumulation of pathogen-associated molecular patterns (PAMPs) that would otherwise activate an inducible immune response through pattern recognition receptors (PRRs). In addition, many of the constitutive mechanisms are known to directly downregulate PAMP signalling through PRRs. Both of these effects limit PRR-induced expression of type I interferon and IL-1β. b | The relationship between the different proposed layers of the immune response. A first layer of defence is exerted by physical and chemical barriers. Constitutive innate immune mechanisms function as soon as a danger signal is detected and eliminate harmful microorganisms and host molecules by specific non-inflammatory mechanisms that operate independently of PRRs. This prevents establishment of the infection and accumulation of PAMPs, thus limiting the activation of PRR-based inducible innate immune responses. If PRR-based immunity is activated, owing to the level of PAMPs exceeding a certain threshold, this leads to inflammation and promotes activation of the adaptive immune response mediated by T cells and antibodies. IRF, interferon regulatory factor.

Fig. 3. Overview of the regulation of microbial replication by constitutive innate immune mechanisms.

a | Constitutive innate immune mechanisms and viral infection. The accumulation of specific viral molecular structures (such as double-stranded RNA (dsRNA) or capsids) and cellular stress responses (such as autophagy) activate constitutive–latent mechanisms with direct antiviral activity, independently of pattern recognition receptors. Some of the antiviral effector functions target microbial replication by blocking specific steps in the replication cycles of viruses; these effectors include soluble lectins, antimicrobial peptides, restriction factors, RNA interference (RNAi) and metabolites. Other antiviral effectors of the constitutive response function through the degradation of virus particles; these include nucleases such as TREX1, which degrades viral DNA in the cytoplasm, and RNase L, which degrades viral RNA, as well as autophagy and proteasomal degradation. Viruses can be targeted for proteasomal degradation by the ubiquitin E3 ligase TRIM21, which binds to antibody-attached viral capsids. b | Constitutive innate immune mechanisms and bacterial infection. The presence of bacteria changes the local microenvironment, for example through the accumulation of hydrophobic and charged bacterial surfaces or alteration of cellular metabolism. This activates antibacterial activities independently of pattern recognition receptors, including inactivation by soluble lectins and antimicrobial peptides, nutritional depletion by natural resistance-associated macrophage protein 1 (NRAMP1) and lactoferrin, and bacterial degradation by phagocytosis and basal autophagy. dsDNA, double-stranded DNA; RISC, RNA-induced silencing complex; ROS, reactive oxygen species; viRNA, virus-derived small interfering RNA.

Fig. 4. Constitutive control of microbial replication by restriction factors and autophagy.

a | Restriction factors that control herpesvirus and retrovirus infections, including their targets in the viral replication cycle. Restriction factors interfere with viral replication by either blocking a specific and essential step in the viral replication cycle (for example, viral gene transcription or release of progeny virus) or depletion of factors that are essential for replication (such as deoxynucleoside triphosphates). b | Blockade of viral and bacterial replication by autophagy. Various ubiquitin E3 ligases (such as SMURF1, LRSAM1 and TRIM23) and ubiquitin-binding proteins (such as p62, optineurin and NDP52) have been identified to conjugate ubiquitin to microbial surfaces, which targets them for loading into autophagosomes. Also, cytosolic exposure of glycans by pathogen-damaged vesicles can be recognized by galectin 8 for targeting to autophagosomes. APOBEC3, apolipoprotein B mRNA-editing complex 3; BST2, bone marrow stromal antigen 2 (also known as tetherin); DBR1, RNA lariat debranching enzyme 1; IFI16, interferon-γ-inducible protein 16; IFITM, interferon-induced transmembrane protein; MTOC, microtubule-organizing centre; ND10, nuclear domain 10; SAMHD1, SAM domain and HD domain-containing protein 1; SIRT6, sirtuin 6; SNORA31, small nucleolar RNA, H/ACA box 31.