Association of T-Zone Reticular Networks and Conduits with Ectopic Lymphoid Tissues in Mice and Humans

Abstract

Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial venules, and follicular dendritic cells; and are organized in lymph node–like structures. Although fibroblastic stromal cells may play a role in TLT induction and persistence, they have remained poorly defined. Herein, we report that TLTs arising during inflammation in mice and humans in a variety of tissues (eg, pancreas, kidney, liver, and salivary gland) contain stromal cell networks consisting of podoplanin+ T-zone fibroblastic reticular cells (TRCs), distinct from follicular dendritic cells. Similar to lymph nodes, TRCs were present throughout T-cell–rich areas and had dendritic cells associated with them. They expressed lymphotoxin (LT) β receptor (LTβR), produced CCL21, and formed a functional conduit system. In rat insulin promoter–CXCL13–transgenic pancreas, the maintenance of TRC networks and conduits was partially dependent on LTβR and on lymphoid tissue inducer cells expressing LTβR ligands. In conclusion, TRCs and conduits are hallmarks of secondary lymphoid organs and of well-developed TLTs, in both mice and humans, and are likely to act as important scaffold and organizer cells of the T-cell–rich zone.

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

“…FRCs are found in inflammatory diseases in organized tertiary lymphoid tissues where there is a substantial lymphocytic infiltrate (eg, the salivary gland in Sjogren syndrome and the liver in primary biliary cirrhosis). 44 In contrast, the SSc skin fibroblast transition usually appears in lieu of major classic lymphocytic infiltrates. We postulate…”

Lymphatic vessels and tertiary lymphoid organs

“…TLOs are characterized by their cellular, organizational, chemokine, and vascular similarity to SLOs, especially LNs. These similarities include T and B cell compartmentalization, APCs such as DCs and follicular DCs, stromal cells (5), conduits, and a highly organized vascular system of HEVs and LVs (see below) (5,22,23). Common features of TLOs and LNs are depicted in Figure 1.…”

CD4+ follicular helper T cell infiltration predicts breast cancer survival

“…In secondary lymphoid organs, such as LNs, CXCL13 is expressed by stromal cells and Th cells in GC, with its ectopic expression promoting lymphoid neogenesis (40). A comparison of CXCL13 expression with other cytokines/chemokines in an extensively and a minimally infiltrated tumor ( Figure 7C) showed that the majority were expressed by infiltrating leukocytes (CD14 + monocytes, CD4 + T cells, or the remaining mixture of CD45 + cells) but not the EpCAM + epithelial/tumor cells.…”