Lymph node stromal cells (LNSCs) have been shown to be mediators of antigen-specific peripheral T cell tolerance through the expression of peripheral tissue antigens (PTAs). However, the specific cell subsets involved were not known. Now, two papers published in the Journal of Experimental Medicine have identified these cell subsets and some of the PTAs that they express, highlighting the importance of diverse LNSC subsets in maintaining peripheral tolerance.

Peripheral tolerance is the process by which self-reactive T cells that have escaped negative selection in the thymus are rendered anergic or deleted in the periphery. Analyses of the lymph node stromal compartment by both groups identified four phenotypically different cell subsets based on their expression of gp38 and CD31: fibroblastic reticular cells (FRCs; gp38+CD31−), blood endothelial cells (BECs; gp38−CD31+), lymphatic endothelial cells (LECs; gp38+CD31+) and a poorly studied population of double negative cells (gp38−CD31−). Of note, only the double negative cell subset expressed the transcription factor autoimmune regulator (AIRE), which is known to be crucial for the expression of numerous PTAs by thymic epithelial cells.

To further understand the role of LNSC subsets in peripheral tolerance, the groups used different systems to examine the induction of self tolerance to specific PTAs by each subset. The melanocyte-specific protein tyrosinase (TYR) was shown to be expressed by LECs but not by other LNSCs, and Cohen et al. showed that these cells induced proliferation of TYR-specific CD8+ T cells, which is known to occur before T cell deletion in vivo. Using a model system in which LNSCs could express ovalbumin (OVA) as a PTA, Fletcher et al. showed that it was the FRCs that predominantly presented this antigen to the corresponding CD8+ T cells, resulting in the T cell proliferation that leads to deletion in this model. So, these data show that specific LNSC subsets can act as antigen-presenting cells for the induction of peripheral tolerance.

Furthermore, several other PTAs were shown to be specifically expressed by distinct LNSC subsets. FRCs expressed the melanocyte-specific antigen MLANA (also known as MART1) and prepro-insulin 2, whereas BECs specifically expressed retinol S antigen. In addition to TYR, LECs expressed the intestinal epithelial cell-specific antigen A33 and the pancreatic polypeptide PPY. Other PTAs were shown to be expressed by all four subsets, highlighting the complexity and specificity of PTA expression by LNSCs.

Through the administration of the Toll-like receptor 3 ligand polyinosinic–polycytidylic acid (polyI:C), Fletcher et al. showed that PTA expression by FRCs was reduced and that stimulation of cognate T cells was decreased during inflammation. They propose that the decreased ability of FRCs to stimulate CD8+ T cells may be a mechanism to protect lymph node structure and function during an inflammatory response.

Together, these studies show that LNSCs of distinct origin, phenotype and function can express distinct endogenous antigens and potentially act as mediators of peripheral tolerance.