Abstract
Lymph nodes are secondary lymphoid organs in which immune responses of the adaptive immune system are initiated and regulated. Distributed throughout the body and embedded in the lymphatic system, local lymph nodes are continuously informed about the state of the organs owing to a constant drainage of lymph. The tissue-derived lymph carries products of cell metabolism, proteins, carbohydrates, lipids, pathogens and circulating immune cells. Notably, there is a growing body of evidence that individual lymph nodes differ from each other in their capacity to generate immune responses. Here, we review the structure and function of the lymphatic system and then focus on the factors that lead to functional heterogeneity among different lymph nodes. We will discuss how lymph node heterogeneity impacts on cellular and humoral immune responses and the implications for vaccination, tumour development and tumour control by immunotherapy.
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Acknowledgements
The authors thank the WÜSI principal investigators, A. Riedel, M. Bajénoff and the Kastenmüller Lab for the critical reading of the manuscript. Our research is supported by the European Research Council (ERC) (819329- STEP2), the German Research Foundation (DFG) (SFB 1583- DECIDE and GRK2581 ‘SPHINGOINF’) and the Max Planck Society (Max Planck Research Groups).
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Glossary
- Affinity maturation and antibody class switching
-
Affinity maturation and antibody class switching are two important mechanisms B cells use to improve the efficacy of the antibody response. Once B cells have recognized their cognate antigen through the B cell receptor (BCR), they start producing IgM antibodies and this is known as the primary response. To increase the binding affinity of the BCR to cognate antigen, B cells introduce mutations into the complementarity-determining region of the BCR via a process known as somatic hypermutation (SHM). SHM produces B cells with varying affinities of BCRs, and only the ones with the strongest affinity are positively selected by follicular helper T cells in germinal centres. During antibody class switching, changes occur in the heavy-chain domain of the antibody, creating antibodies with similar affinity but different effector functions. This process involves recombining the exon clusters on the IgH locus, enabling antibody isotype switching (for example, from IgM to IgG, IgE or IgA).
- Aryl hydrocarbon receptor
-
(AhR). A ligand-activated transcription factor, which upon ligand binding translocates from the cytoplasm to the nucleus, forms a complex with aryl hydrocarbon receptor nuclear translocator and induces transcription of target genes. In its inactive state, it forms a protein dimer complex with HSP90, XAP2, p23 and SRC. AhR has diverse roles in adaptive immune responses, such as promoting Th17 cell induction or Treg cell stabilization.
- Central Treg cells
-
Treg cells can be classified either on their developmental origin — as tTreg and pTreg cells — or based on their migratory pattern — as central Treg and effector Treg cells. Central Treg cells primarily recirculate in the blood and SLOs. They are characterized by a CD4+CD25+FOXP3+CD44lowCD62LhighCCR7+ phenotype and primarily localize to the T cell zone in the spleen and lymph nodes. They require IL-2 for their homoeostasis and survival and serve as a pool of long-lived recirculating Treg cells in SLOs.
- Effector Treg cells
-
Effector Treg cells develop from central Treg cells in a BATF-dependent manner and require ICOS signalling for their survival. Even though inflammatory signals primarily drive the differentiation of effector Treg cells from central Treg cells, constant T cell receptor stimulation is required for the maintenance of effector Treg cells. These Treg cells have a CD4+CD25+FOXP3+CD44highCD62LlowCCR7− phenotype and primarily localize to non-lymphoid tissues.
- Exosomes
-
Exosomes are single-membraned extracellular vesicles that are produced by cells in the endoplasmic reticulum and can carry different types of cargo from nucleic acids to proteins or metabolites. They are critical components in cellular communications both over short and long distances.
- Hyaluronic acid
-
Hyaluronic acid is a large polysaccharide formed of glucuronic acid and glucosamine, with an approximate relative molecular weight of 105–107 (ratio of the molecular weights of hyaluronic acid and carbon). It is produced by distinct cell types and is the main component of the extracellular matrix.
- Sphingosine-1-phosphate
-
(S1P). A sphingolipid that is formed from ceramide by the action of ceramidase and sphingosine kinases (SK1 and SK2). S1P acts as a crucial mediator in lymphocyte trafficking, vascular development and heart development via its receptors S1PR1–S1PR5.
- Tumour secretome
-
The tumour secretome is the entire collection of macromolecules — including both soluble proteins and insoluble vesicles — that take part in cell–cell communication in the tumour (for example, growth factors, lipids and exosomes).
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Cruz de Casas, P., Knöpper, K., Dey Sarkar, R. et al. Same yet different — how lymph node heterogeneity affects immune responses. Nat Rev Immunol 24, 358–374 (2024). https://doi.org/10.1038/s41577-023-00965-8
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DOI: https://doi.org/10.1038/s41577-023-00965-8
