Lymph node stroma broaden the peripheral tolerance paradigm

Abstract

Research into how self-reactive T cells are tolerized in lymph nodes has focused largely on dendritic cells (DCs). We now know that lymph node stromal cells (LNSC) are important mediators of deletional tolerance to peripheral tissue-restricted antigens (PTAs), which are constitutively expressed and presented by LNSCs. Of the major LNSC subsets, fibroblastic reticular cells and lymphatic endothelial cells are known to directly induce tolerance of responding naïve CD8 T cells. The biological outcome of this interaction fills a void otherwise not covered by DCs or thymic stromal cells. These findings, we suggest, necessitate a broadening of peripheral tolerance theory to include steady-state presentation of clinically relevant PTA to naïve CD8 T cells by lymph node-resident stroma.

Figure 1. T cells interact with multiple lymph node stromal cell types known to express peripheral tissue-restricted antigens

A. Most T cells enter the lymph node from the bloodstream through HEV lined by specialized blood endothelial cells in the paracortex. B. While in the lymph node, T cells crawl throughout the paracortex on the extensive FRC network, interacting with antigen-bearing dendritic cells. C. T cells interact with lymphatic endothelial cells. This occurs occasionally as the route of entry to the lymph node through afferent lymphatics for some activated T cells, and very commonly as an exit route through efferent lymphatics for naïve T cells. T cell interaction with other stromal subsets, including FDC and eTAC is likely to occur but is not well defined. FRC: fibroblastic reticular cell. FDC: follicular dendritic cell. eTAC: extra-thymic Aire-expressing cell. ECM: extracellular matrix. HEV: high endothelial venule.