Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions

Abstract

Lymph node stromal cells (LNSCs) can induce potent, antigen-specific T cell tolerance under steady-state conditions. Although expression of various peripheral tissue–restricted antigens (PTAs) and presentation to naive CD8+ T cells has been demonstrated, the stromal subsets responsible have not been identified. We report that fibroblastic reticular cells (FRCs), which reside in the T cell zone of the LN, ectopically express and directly present a model PTA to naive T cells, inducing their proliferation. However, we found that no single LNSC subset was responsible for PTA expression; rather, each subset had its own characteristic antigen display. Studies to date have concentrated on PTA presentation under steady-state conditions; however, because LNs are frequently inflammatory sites, we assessed whether inflammation altered stromal cell–T cell interactions. Strikingly, FRCs showed reduced stimulation of T cells after Toll-like receptor 3 ligation. We also characterize an LNSC subset expressing the highest levels of autoimmune regulator, which responds potently to bystander inflammation by up-regulating PTA expression. Collectively, these data show that diverse stromal cell types have evolved to constitutively express PTAs, and that exposure to viral products alters the interaction between T cells and LNSCs.

Immortalized clones of fibroblastic reticular cells activate virus-specific T cells during virus infection

“…FRCs Activate Naive LCMV-Specific T Cells but Limit Expansion of Activated LCMV-Specific T Cells. FRCs display peripheral tissue antigens to CD8 + T cells (13,29); however, there is no published data regarding their ability to present antigen from infectious virus. Furthermore, because MHC II has not previously been described on FRCs, there has been no study of their ability to present antigen to CD4 + T cells.…”

“…Abrogation of FRC-T-cell interactions results in Tcell loss (12). Furthermore, FRCs may contribute to the maintenance of peripheral CD8+ T-cell tolerance as they are able to present peripheral endogenous antigens (13,14) and, further, may induce deletion of CD8+ T cells specific to these antigens (15).…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…This mirrors the central tolerance maintaining functions of medullary thymic epithelial cells, which exhibit promiscuous gene expression and thereby express antigen from all tissues of the body to deactivate self-reactive T cells through deletion (recessive tolerance) and T Reg cell induction (dominant tolerance) [88]. Thus, the LN stromal cells hold intrinsic, tissue-specific capabilities that likely play similar roles in peripheral tolerance as thymic epithelial cells play in central tolerance [7,[89][90][91].…”

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

“…Furthermore, the data ruled out the possibility that non-activated endothelial cells are a passive barrier, without a role in lymphocyte migration. Finally, one possible explanation for the lack of differential lymphocyte transmigration through the two different types of endothelium (the only exceptions being CD4 + T central memory cells and memory unswitched B cells) is the similar level of VCAM-1 found on BEC-and LEC-cell surface [31]. These transmigration data only apparently contradict previously published results demonstrating a reduced transmigration of lymphocytes obtained from natalizumab-treated patients [27,28] because these studies were obtained using very different experimental conditions, including the use of purified lymphocyte subsets and of human brain microvascular endothelial cells, activated with different stimuli.…”