Abstract
The blood vasculature regulates both the development and function of secondary lymphoid organs by providing a portal for entry of hemopoietic cells. During the development of lymphoid organs in the embryo, blood vessels deliver lymphoid tissue inducer cells that initiate and sustain the development of lymphoid tissues. In adults, the blood vessels are structurally distinct from those in other organs due to the requirement for high levels of lymphocyte recruitment under non-inflammatory conditions. In lymph nodes (LNs) and Peyer’s patches, high endothelial venules (HEVs) especially adapted for lymphocyte trafficking form a spatially organized network of blood vessels, which controls both the type of lymphocyte and the site of entry into lymphoid tissues. Uniquely, HEVs express vascular addressins that regulate lymphocyte entry into lymphoid organs and are, therefore, critical to the function of lymphoid organs. Recent studies have demonstrated important roles for CD11c+ dendritic cells in the induction, as well as the maintenance, of vascular addressin expression and, therefore, the function of HEVs. Tertiary lymphoid organs (TLOs) are HEV containing LN-like structures that develop inside organized tissues undergoing chronic immune-mediated inflammation. In autoimmune lesions, the development of TLOs is thought to exacerbate disease. In cancerous tissues, the development of HEVs and TLOs is associated with improved patient outcomes in several cancers. Therefore, it is important to understand what drives the development of HEVs and TLOs and how these structures contribute to pathology. In several human diseases and experimental animal models of chronic inflammation, there are some similarities between the development and function of HEVs within LN and TLOs. This review will summarize current knowledge of how hemopoietic cells with lymphoid tissue-inducing, HEV-inducing, and HEV-maintaining properties are recruited from the bloodstream to induce the development and control the function of lymphoid organs.
Highlights
Secondary lymphoid organs (SLOs) are sites in which immune responses are initiated and maintained in order to generate protective immunity against exogenous pathogens and tolerance to self-antigens and commensal organisms [1, 2]
The increase in size of the high endothelial venules (HEVs) network and associated increase in lymph nodes (LNs) cellularity and volume is due, in part, to the release of angiogenic stimuli such as VEGF-A by fibroblast reticular cells (FRCs) and dendritic cells (DCs) [65, 66]. These findings suggest that the differentiation of fully functional, peripheral node addressin (PNAd)-expressing HEV and the expansion of the HEV network are controlled by different types of CD11c+ cells in adult mice
Co-expression of both LTα and LTβ and consequent lymphotoxin β receptor (LTβR) signaling in the exocrine pancreas is required to develop large, organized lymphoid aggregates that contain HEV expressing PNAd at the luminal surface and, as in LNs, these ectopic Tertiary lymphoid organs (TLOs) are highly enriched in L-selectinexpressing T and B lymphocytes
Summary
Secondary lymphoid organs (SLOs) are sites in which immune responses are initiated and maintained in order to generate protective immunity against exogenous pathogens and tolerance to self-antigens and commensal organisms [1, 2]. Vascular changes in antigen-stimulated LNs are accompanied by increased growth of afferent lymphatics and remodeling of the FRC network that alters the availability of chemokines for presentation by HEVs. For example, the dramatic reduction in CCL21 and CXCL13 expression by LN stroma following viral or bacterial infection [110] impacts on T and B lymphocyte recruitment since stromal cell-derived chemokines are presented by HEVs to blood-borne lymphocytes [32].
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