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TLR-dependent T cell activation in autoimmunity

Nature Reviews Immunology volume 11, pages 807–822 (2011)Cite this article

Subjects

Key Points

  • Toll-like receptors (TLRs) are members of the pattern recognition receptor (PRR) family. They sense pathogen-derived molecules termed pathogen-associated molecular patterns (PAMPs), as well as endogenous molecules termed damage-associated molecular patterns (DAMPs) that are released from dead and dying cells. Activation of TLR signalling pathways in innate immune cells, such as dendritic cells (DCs), drives adaptive immunity by enhancing the ability of DCs to act as antigen-presenting cells and promoting the production of pro-inflammatory cytokines that direct the induction of different T cell subtypes.

  • Autoimmune diseases can develop as a result of a breakdown in immune tolerance that leads to the activation of autoantigen-specific T cells. Self-reactive T cells that secrete interleukin-17 (TH17 cells), interferon-γ (TH1 cells) or both cytokines mediate inflammatory pathology in many autoimmune diseases.

  • Infectious pathogens and the gut microbiota have been implicated in precipitating or exacerbating autoimmune diseases in humans. Studies in mouse models and with tissues from patients with autoimmune diseases have suggested that PAMPs may promote innate and consequently adaptive immune responses that promote inflammation and tissue damage.

  • The release of endogenous DAMPs from host cells that have been killed as a result of damage or infection with pathogens can activate innate immune responses, driving sterile inflammation that initiates or exacerbates pathology in autoimmune diseases.

  • Inhibition of agonist binding to TLRs or downstream signalling pathways is a promising approach for the development of therapies for inflammatory and autoimmune diseases.

Abstract

Autoimmune disease can develop as a result of a breakdown in immunological tolerance, leading to the activation of self-reactive T cells. There is an established link between infection and human autoimmune diseases. Furthermore, experimental autoimmune diseases can be induced by autoantigens that are administered together with complete Freund's adjuvant, which contains killed Mycobacterium tuberculosis; in some cases, these bacteria can be replaced by individual pathogen-associated molecular patterns (PAMPs). Exogenous PAMPs and endogenous danger signals from necrotic cells bind to pattern recognition receptors (including Toll-like receptors) and activate signalling pathways in innate immune cells and in T cells. This leads to pro-inflammatory cytokine production and T cell activation, which are now considered to be major factors in the development of autoimmunity.

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Figure 1: Bacterium-induced signalling in innate immune cells leads to cytokine production that promotes the activation of T cells.
Figure 2: Effector cells and drug targets in autoimmunity.
Figure 3: Indirect and direct activation of T cells by TLR agonists.
Figure 4: PAMP-, DAMP- and MAMP-mediated activation of autoimmune responses.

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Acknowledgements

Kingston Mills is supported by Science Foundation Ireland, The Irish Health Research Board and Enterprise Ireland. I am grateful to J. Fletcher, C. Sutton and R. Higgs for helpful discussions.

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  1. Immunology Research Centre and School of Biochemistry and Immunology, Trinity College, Dublin, Ireland

    Kingston H. G. Mills

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Kingston Mills is a co-founder and shareholder in Opsona Therapeutics Ltd and TriMod Therapeutics Ltd, which are university spin-out companies involved in the development of immunotherapeutics.

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Glossary

Microorganism-associated molecular patterns

(MAMPs). Molecular patterns that are found in pathogens and commensal microorganisms but not in mammalian cells.

Damage-associated molecular patterns

(DAMPs). Molecular patterns that are found in mammalian cells and are released as a result of cellular stress, cellular damage or non-physiological cell death. Examples include hyaluronate (which is released from the degraded stroma); HMGB1 (which is released from the nucleus); and ATP, uric acid, S100 calcium-binding proteins and heat-shock proteins (which are released from the cytosol). Such DAMPs are thought to elicit local inflammatory reactions.

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in pathogens but not in mammalian cells. Examples include terminally mannosylated and polymannosylated compounds (which bind the mannose receptor) and various microbial components, such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin and double-stranded RNA (all of which bind Toll-like receptors).

Sterile inflammation

Inflammation, characterized by leukocyte recruitment, that does not involve infection but is precipitated by the activation of innate immune cells by endogenous mediators (alarmins or DAMPs) that are released from host cells following tissue injury and necrotic cell death.

NLRP3 inflammasome

(Nucleotide-binding oligomerization domain-, leucine rich repeat- and pyrin domain-containing 3 inflammasome). The NLRP proteins are a family of cytoplasmic proteins that can form high molecular weight signalling complexes, termed inflammasomes. The NLRP3 inflammasome contains the adaptor molecule ASC and recruits pro-caspase 1, which is then activated by autocatalytic cleavage. Active caspase 1 catalyses the cleavage of pro-IL-1β, pro-IL-18 and pro-IL-33, resulting in the secretion of biologically active forms of these cytokines. The NLRP3 inflammasome mediates innate immune responses to exogenous bacteria, environmental molecules (such as alum and asbestos) and endogenous molecules (such as ATP and amyloid-β).

Lymphoid tissue inducer-like cells

Innate lymphoid cells that constitutively express CD4, RORγt, the IL-23 receptor, the aryl hydrocarbon receptor and CCR6, but not CD3, NK1.1, CD11b, GR1, CD11c or B220. These cells are found in the spleen and the lamina propria and are an early source of IL-17 and IL-22 in host defence and an important source of IL-22 in intestinal homeostasis.

Specific pathogen free conditions

(SPF conditions). Vivarium conditions for rodents in which an increasing number of pathogens are excluded or eradicated from the colony. These animals are maintained in the absence of most of the known chronic and latent persistent pathogens. Although this enables better control of experimental conditions related to immunity and infection, it also sets apart such animal models from pathogen-exposed humans or non-human primates, whose immune systems are in constant contact with infectious agents.

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Mills, K. TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol 11, 807–822 (2011). https://doi.org/10.1038/nri3095

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