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  • Review Article
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The stromal and haematopoietic antigen-presenting cells that reside in secondary lymphoid organs

Key Points

  • Antigen presentation by dendritic cells (DCs) is the driving force that induces naive T cells to differentiate into effector and memory T cells, but it can also lead to different forms of tolerance depending on the functional status of the DCs.

  • Self-reactive T cells can also encounter their cognate antigens presented by non-haematopoietic stromal cells.

  • In secondary lymphoid organs (SLOs), antigens are presented to T cells by DCs, B cells, basophils and stromal cells. These can be migratory cells that enter through the blood (B cells and basophils) or lymph (DCs), or they can be permanent residents of the SLO (DCs and stromal cells).

  • Lymph node-resident DCs sample lymph-borne antigens either directly, from the subcapsular or medullary sinuses, or from the lymph-draining conduit system. Lymph node-resident DCs can also acquire tissue-derived antigens from migratory DCs that enter the lymph node through afferent lymphatics and migrate into the paracortex. Spleen-resident DCs acquire blood-borne antigens either directly from the marginal sinuses or indirectly from macrophages that line the marginal sinuses.

  • Lymph node stromal cells are also potent antigen-presenting cells that express peripheral tissue-restricted antigens and directly present them to naive T cells, resulting in T cell tolerance. Lymph node stromal cells can also influence T cell responses to lymph-borne and blood-borne antigens.

  • Peripheral tissue-restricted antigen expression in the lymph nodes is not restricted to a single subset of lymph node stromal cells. Rather, fibroblastic reticular cells, lymphatic endothelial cells and blood endothelial cells, as well as two rare stromal cell subsets — double-negative stromal cells and extrathymic Aire-expressing cells — all have a unique capacity to express different self antigens.

Abstract

T cells encounter their cognate antigens in specialized compartments of secondary lymphoid organs (SLOs). There, dendritic cells (DCs) present self and non-self antigens to T cells, and promote immunity or tolerance depending on the availability of danger signals. Resident stromal cells orchestrate the interaction between T cells and DCs by recruiting them to T cell zones and guiding their migration within SLOs. Recent studies have shown that SLO-resident stromal cells also have a crucial role in tolerance induction in the periphery. In this Review, we discuss the roles of SLO-resident DCs and stromal cells in shaping T cell responses.

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Figure 1: Stromal cell populations in lymph nodes.
Figure 2: Role of lymph node-resident stromal cells in peripheral T cell tolerance.

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Acknowledgements

The authors thank D. Malhotra for thoughtful suggestions on the manuscript. We apologize to those authors who could not be cited here owing to space limitations. This work was supported by US National Institutes of Health grants R01 DK074500 and P01 AI045757 (to S.J.T.), the American Association for Cancer Research Centennial Postdoctoral Fellowship in Cancer Research (to K.G.E.) and a National Health Medical Research Council Postdoctoral Biomedical Training Fellowship (to A.L.F.).

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Glossary

High endothelial venules (HEVs).

These are specialized post-capillary venules with a cuboidal endothelial lining that occur in all secondary lymphoid organs, except for the spleen. HEVs allow the continuous transmigration of lymphocytes owing to the constitutive expression of adhesion molecules and chemokines at their luminal surface.

Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of CD8+ T cell responses to viruses that do not infect antigen-presenting cells.

Autophagy

An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation, through fusion to secondary lysosomes.

Peripheral tissue-restricted antigens

These are non-circulatory self antigens expressed by five or fewer types of tissue. In lymphoid tissues, the expression of peripheral tissue-restricted antigens was first identified in the thymus as a mechanism of central tolerance for exposing developing thymocytes to an array of organ-restricted, conditionally expressed or otherwise sequestered antigens. The expression of such antigens by lymph node stromal cells was later identified and has been shown to induce peripheral tolerance.

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Turley, S., Fletcher, A. & Elpek, K. The stromal and haematopoietic antigen-presenting cells that reside in secondary lymphoid organs. Nat Rev Immunol 10, 813–825 (2010). https://doi.org/10.1038/nri2886

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