Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease

Key Points

  • To facilitate the encounter between lymphocytes and pathogens, the immune system has developed highly structured environments in the lymph nodes and marginal zones of the spleen.

  • Signalling through the lymphotoxin (LT)/LIGHT pathways are crucial for the maintenance of these environments. These interactions are complex and, although the role of LT in the spleen has been well described, our understanding of its role in lymph nodes and mucosal sites is preliminary.

  • Analysis of the effects of inhibitors of the LT/LIGHT system, which have been shown to reduce disease in many autoimmune models, can help us to understand the influence of lymphoid microenvironments on immune responses.

  • Here, our understanding of the role of LT/LIGHT signalling in the regulation of lymphoid microenvironments in the spleen, lymph nodes and mucosal system, in B- and T-cell function and in disease is discussed. The potential therapeutic benefits of blocking LT/LIGHT signalling is also discussed.

Abstract

Much of the efficiency of the immune system is attributed to the high degree of spatial and temporal organization in the secondary lymphoid organs. Signalling through the lymphotoxin (LT) pathway is a crucial element in the maintenance of this organized microenvironment. The effect of altering lymphoid microenvironments on immune responses remains relatively unexplored. Inhibitors of the LT and LIGHT pathways have been shown to reduce disease in a wide range of autoimmune models. This approach has provided a tool to probe the effect of manipulation of the microenvironment on both normal and pathological immune responses.

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Figure 1: Ligands and receptors of the tumour-necrosis factor/lymphotoxin system.
Figure 2: Maintenance of follicular dendritic cells — a model for lymphotoxin–stromal-cell interactions.
Figure 3: What is the role of lymphotoxin/LIGHT in T-cell function in the lymph nodes?
Figure 4: Organized lymphoid tissue is seen in inflamed ectopic sites.

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Acknowledgements

We wish to thank E. Notidis and P. Hochman for critical reading and C. Ware, P. Rennert, Y-Z. Fu and J. Cyster for many helpful discussions.

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Correspondence to Jeffrey L. Browning.

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DATABASES

Entrez

HSV

LCMV

LocusLink

CCL19

CCL21

CCR7

CD157

CXCL9

CXCL10

CXCL11

CXCL12

CXCL13

CXCR3

HVEM

ICAM1

IFN-γ

IL-12

LIGHT

LTα

LTβ

LTβR

Rag

TNF

VCAM1

Glossary

MARGINAL ZONE

A specialized microenvironment that surrounds the B-cell follicles of the spleen. This compartment is rich in monocytic and dendritic cells that function to capture blood-borne pathogens and present these antigens to both the marginal-zone and memory B cells that reside in this space.

LYMPHOID ARCHITECTURE

The anatomical framework of the lymphoid organs, including the vascular and lymphatic conduits, extracellular matrix, reticular divisions between various regions and the compartmentalization of cellular subsets.

ECTOPIC LYMPHOID STRUCTURES

Organized lymphocytic aggregates that form in sites of chronic inflammation. Typically, T- and B-cell-rich zones are segregated, and dendritic cells (DCs), germinal centres with follicular DC (FDC) networks and specialized endothelia are present. These structures are also known as the 'tertiary immune system' and their formation is termed 'lymphoid neogenesis'.

MICROENVIRONMENT

The generic term used to describe the local interplay between mobile lymphocytes and the fixed reticular/stromal cells, and includes cell adhesion, trafficking, chemokine function and cellular positioning.

LYMPHOID FOLLICLE

A region in organized lymphoid environments that is composed of B cells. Typically, a follicular dendritic-cell (FDC) reticular network marks this region. Germinal-centre reactions occur in this region. The term primary follicle (or mantle in humans) refers to the region that contains follicular B cells that remain outside the germinal centres.

GERMINAL CENTRE

Also known as a secondary follicle, this highly specialized and dynamic microenvironment occurs in the lymphoid follicles during an immune response. This environment is designed to promote the presentation of unprocessed antigen, the rapid clonal expansion of activated B cells, somatic hypermutation and affinity maturation that culminates in the generation of memory B cells and antibody-secreting plasma cells.

FOLLICULAR DENDRITIC-CELL NETWORK

(FDC network). A meshwork of specialized reticular fibroblasts that has the unique ability to retain and present intact antigen to B cells, as well as to provide specific survival and positioning signals.

CROHN'S DISEASE

One of the two main forms of inflammatory bowel disease that afflicts human patients. The pathophysiology is unknown, but is presumed to stem from a dysequilibrium between the gut flora and the mucosal immune system.

ALTERNATIVE NUCLEAR FACTOR-κB PATHWAY (NF-κB).

Signalling through lymphotoxin-β receptor can activate NF-κB through a non-canonical NF-κB-inducing kinase (NIK)–inhibitor of NF-κB kinase-α (IKKα)-dependent route that results in the activation of RelB/NF-κB2. The repertoire of RelB/NF-κB2-activated genes is presumably different from those that are activated by the classic NF-κB complexes.

AFFINITY MATURATION

The mutation of antibody variable-region genes followed by the selection of higher-affinity variants in the germinal centre leads to an increase in antibody affinity as an immune response progresses. The selection is thought to be a competitive process in which B cells compete with free antibody to capture decreasing amounts of antigen.

SOMATIC HYPERMUTATION

The accumulation of point mutations in the variable-region genes encoding immunoglobulin heavy and light chains, giving rise to high-affinity antibodies that are specific for a given antigen — a process known as affinity maturation. B cells that express high-affinity immunoglobulins on their cell surface are selected by limited amounts of the antigens.

NON-OBESE DIABETIC MICE

(NOD mice). A strain of mice that normally develop idiopathic autoimmune diabetes that closely resembles type I diabetes in humans. The target antigen(s) that is recognized by the pathogenic CD4+ T cells that initiate disease is expressed by pancreatic-islet cells, but its identity has remained elusive.

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Gommerman, J., Browning, J. Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease. Nat Rev Immunol 3, 642–655 (2003). https://doi.org/10.1038/nri1151

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