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  • Review Article
  • Published:

Lymphotoxin signalling in immune homeostasis and the control of microorganisms

Nature Reviews Immunology volume 13, pages 270–279 (2013)Cite this article

Subjects

Key Points

  • Lymphotoxin is best known for its roles in promoting lymphoid tissue development, but this cytokine also has other important immunological functions.

  • Lymphotoxin produced by dendritic cells has steady-state immunological functions, including roles in maintaining the cellularity of secondary lymphoid organs and in IgA production.

  • The coordination of the multicellular interactions that contribute to T helper cell and germinal centre responses depends on the lymphotoxin pathway.

  • Antiviral immunity requires the lymphotoxin pathway, both for the regulation of type I interferon production and for innate aspects of the B cell response.

  • Innate lymphoid cells produce lymphotoxin and this promotes interleukin-23 (IL-23)- and IL-22-dependent immune responses at mucosal surfaces. Lymphotoxin production at mucosal surfaces also regulates the microbiota and can contribute to metabolic disease.

  • The lymphotoxin pathway has a crucial role in active immune responses that occur in adult hosts, and a better understanding of these roles may help to guide the development of a new class of therapeutic agents to treat inflammatory diseases.

Abstract

Lymphotoxin (LT) is a member of the tumour necrosis factor (TNF) superfamily that was originally thought to be functionally redundant to TNF, but these proteins were later found to have independent roles in driving lymphoid organogenesis. More recently, LT-mediated signalling has been shown to actively contribute to effector immune responses. LT regulates dendritic cell and CD4+ T cell homeostasis in the steady state and determines the functions of these cells during pathogenic challenges. The LT receptor pathway is essential for controlling pathogens and even contributes to the regulation of the intestinal microbiota, with recent data suggesting that LT-induced changes in the microbiota promote metabolic disease. In this Review, we discuss these newly defined roles for LT, with a particular focus on how the LT receptor pathway regulates innate and adaptive immune responses to microorganisms.

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Figure 1: The LT pathway regulates DC fates.
Figure 2: LT coordinates adaptive immunity.
Figure 3: Regulation of viral infections with LT.
Figure 4: LT regulates responses to microorganisms at mucosal surfaces.

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Acknowledgements

The authors would like to thank A. Tumanov and M. Zhu for their contribution to the lymphotoxin project. This work is partially supported by DK080736 and CA141975 to Y.-X.F.

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  1. Department of Pathology, University of Chicago, 924 East 57 Street, Chicago, 60637, Illinois, USA

    Vaibhav Upadhyay & Yang-Xin Fu

  2. Committee on Immunology, University of Chicago, 924 East 57 Street, Chicago, 60637, Illinois, USA

    Yang-Xin Fu

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(ILCs). Populations of lymphoid cells that lack lineage markers typically associated with other immune cell subsets, but that express transcription factors and cytokines that are usually associated with differentiated CD4+ T helper cell subsets.

Cd11c–DTR system

A system in which mice express the diphtheria toxin receptor (DTR) under the control of the Cd11c gene promoter. This allows the conditional depletion of dendritic cells (and some other CD11c+ cells) in response to diphtheria toxin administration.

μMT−/− mice

Mice that contain a targeted mutation of Ighm; these mice lack mature, conventional B cells.

LTR-Ig and TNFR-Ig

LTR-Ig and TNFR-Ig are decoy receptors for the lymphotoxin receptor (LTR) and the tumour necrosis factor receptor (TNFR), respectively. Their administration prevents ligand–receptor interactions and circumvents signalling through these pathways. They block lymphoid organogenesis if delivered in utero.

Subcapsular sinus (SCS) macrophages

CD11b+CD169+ macrophages that populate the subcapsular sinus of lymph nodes.

Lymphoid tissue-inducer cells

A CD4+CD90+RORγt+CD3− subset of innate lymphoid cells that express lymphotoxin-α1β2 to enable the formation of lymph nodes and Peyer's patches during development.

16S rRNA

A component of the 30S subunit of the bacterial ribosome; a unique secondary structure characterized by stem and loop regions makes this target useful in the unbiased identification of currently uncultured commensal bacteria.

Segmented filamentous bacteria

(SFB). A bacterial species that lives in the terminal ileum in direct contact with intestinal epithelial cells and that induces the expression of interleukin-17A (IL-17A), IL-22 and IgA in the host. Candidatus savagella has been proposed as a name for this uncultured species.

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Upadhyay, V., Fu, YX. Lymphotoxin signalling in immune homeostasis and the control of microorganisms. Nat Rev Immunol 13, 270–279 (2013). https://doi.org/10.1038/nri3406

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