Secondary lymphoid organs are integral to initiation and execution of adaptive immune responses. These organs provide a setting for interactions between antigen-specific lymphocytes and antigen-presenting cells recruited from local infected or inflamed tissues. Secondary lymphoid organs develop as a part of a genetically preprogrammed process during embryogenesis. However, organogenesis of secondary lymphoid tissues can also be recapitulated in adulthood during de novo lymphoid neogenesis of tertiary lymphoid structures (TLSs). These ectopic lymphoid-like structures form in the inflamed tissues afflicted by various pathological conditions, including cancer, autoimmunity, infection, or allograft rejection. Studies are beginning to shed light on the function of such structures in different disease settings, raising important questions regarding their contribution to progression or resolution of disease. Data show an association between the tumor-associated TLSs and a favorable prognosis in various types of human cancer, attracting the speculation that TLSs support effective local antitumor immune responses. However, definitive evidence for the role for TLSs in fostering immune responses in vivo are lacking, with current data remaining largely correlative by nature. In fact, some more recent studies have even demonstrated an immunosuppressive, tumor-promoting role for cancer-associated TLSs. In this review, we will discuss what is known about the development of cancer-associated TLSs and the current understanding of their potential role in the antitumor immune response.

Leucocyte (L)-selectin can be proteolytically cleaved in the membrane proximal extracellular region to yield a soluble fragment that contains the functional lectin and epidermal growth factor domains. A variety of stimuli are known to stimulate L-selectin shedding including chemoattractants, phorbol esters, and L-selectin cross-linking; however, the enzymes that regulate L-selectin expression are not characterized. In this study we have used phorbol ester to stimulate endoproteolytic release of L-selectin and identified a major role for a cell surface metalloproteinase (L-selectin sheddase) in this process. The hydroxamic acid-based inhibitor of zinc-dependent matrix metalloproteinases Ro 31-9790 completely prevented shedding of cell surface L-selectin from leucocytes in mouse, rat, and man. L-selectin was susceptible to cleavage by known matrix metalloproteinases. Recombinant human fibroblast collagenase (MMP1) reduced the number of L-selectin-positive lymphocytes to a similar extent as phorbol ester activation, and stromelysin (MMP3) had a partial effect on L-selectin expression. Gelatinases A (MMP2) and B (MMP9) were without effect. Lymphocytes did not express fibroblast collagenase or stromelysin at the cell surface, and tissue inhibitor of metalloproteinases (TIMP) did not affect L-selectin levels. L-selectin sheddase was not detected in media harvested from phorbol ester-stimulated lymphocytes and was only able to cleave L-selectin in the cis but not the trans configuration. These results suggest that endoproteolytic release of L-selectin from the leucocyte surface is mediated by a metalloproteinase (L-selectin sheddase), which is distinguishable from known matrix metalloproteinases. Understanding the regulation of L-selectin sheddase will be critical for controlling leucocyte migration from the blood.

The blood vasculature regulates both the development and function of secondary lymphoid organs by providing a portal for entry of haemopoietic cells. During the development of lymphoid organs in the embryo, blood vessels deliver lymphoid tissue inducer cells which 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 and Peyer’s patches, high endothelial venules (HEV) especially adapted for lymphocyte trafficking form a spatially organised network of blood vessels which controls the both the type of lymphocyte and the site of entry into lymphoid tissues. Uniquely, HEV express vascular addressins which 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 HEV. Tertiary lymphoid organs (TLOs) are HEV containing, lymph node-like structures that develop inside organised tissues undergoing chronic immune-mediated inflammation. In autoimmune lesions, the development of TLOs is thought to exacerbate disease. In cancerous tissues, the development of HEV and TLOs is associated with improved patient outcomes in several cancers. Therefore, it is important to understand what drives the development of HEV 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 in LN and TLOs. This review will summarise current knowledge of how haemopoietic 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.