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

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 03/2010; 207(4):689-97. DOI: 10.1084/jem.20092642
Source: PubMed

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.

Download full-text


Available from: Sophie Acton, Aug 26, 2015
  • Source
    • "Tregs, in turn, prevented immune activation, which was required for graft acceptance. Importantly, in contrast with previous reports (Lee et al., 2007; Nichols et al., 2007; Magnusson et al., 2008; Cohen et al., 2010; Fletcher et al., 2010), in vivo immune regulation by self-antigen-expressing lymph node stromal cells in our transplantation setting was not related to self-reactive T cell deletion, suggesting that lymph node stromal cells may use multiple mechanisms to control self-reactivity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-hematopoietic lymph node stromal cells shape immunity by inducing MHC-I-dependent deletion of self-reactive CD8+ T cells and MHC-II-dependent anergy of CD4+ T cells. In this study, we show that MHC-II expression on lymph node stromal cells is additionally required for homeostatic maintenance of regulatory T cells (Tregs) and maintenance of immune quiescence. In the absence of MHC-II expression in lymph node transplants, i.e. on lymph node stromal cells, CD4+ as well as CD8+ T cells became activated, ultimately resulting in transplant rejection. MHC-II self-antigen presentation by lymph node stromal cells allowed the non-proliferative maintenance of antigen-specific Tregs and constrained antigen-specific immunity. Altogether, our results reveal a novel mechanism by which lymph node stromal cells regulate peripheral immunity. DOI:
    eLife Sciences 11/2014; 3. DOI:10.7554/eLife.04433 · 8.52 Impact Factor
  • Source
    • "Similar to professional bone-marrow-derived APCs, nonimmune cells can present antigen to CD8 + T cells, but this is believed to lead to immune tolerance via T cell deletion or anergy (Bertolino et al., 1995; Cohen et al., 2010; Fletcher et al., 2010; Gardner et al., 2008; Redmond et al., 2005). In line with these reports, we had previously shown that naive CD8 + T cell stimulation by LSECs cross-presenting circulating antigens results in T cell nonresponsiveness toward stimulation via the TCR (Diehl et al., 2008; Limmer et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Development of CD8(+) T cell (CTL) immunity or tolerance is linked to the conditions during T cell priming. Dendritic cells (DCs) matured during inflammation generate effector/memory T cells, whereas immature DCs cause T cell deletion/anergy. We identify a third outcome of T cell priming in absence of inflammation enabled by cross-presenting liver sinusoidal endothelial cells. Such priming generated memory T cells that were spared from deletion by immature DCs. Similar to central memory T cells, liver-primed T cells differentiated into effector CTLs upon antigen re-encounter on matured DCs even after prolonged absence of antigen. Their reactivation required combinatorial signaling through the TCR, CD28, and IL-12R and controlled bacterial and viral infections. Gene expression profiling identified liver-primed T cells as a distinct Neuropilin-1(+) memory population. Generation of liver-primed memory T cells may prevent pathogens that avoid DC maturation by innate immune escape from also escaping adaptive immunity through attrition of the T cell repertoire.
    Cell Reports 03/2013; 3(3). DOI:10.1016/j.celrep.2013.02.008 · 8.36 Impact Factor
  • Source
    • "Inflammation modulates the expression of PTA in LEC, but not in a consistent manner. TLR3 ligation causes LEC, as well as FRC, to downregulate proteolipid protein but upregulate α-fetoprotein (Fletcher et al., 2010). However, double-negative LNSC upregulated both PTA, while BEC upregulated only one. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The lymphatic vasculature provides routes for dendritic cell and lymphocyte migration into and out of lymph nodes. Lymphatic endothelial cells (LEC) control these processes by expression of CCL21, sphingosine-1-phosphate, and adhesion molecules. LEC express MHC-I and MHC-II, but not costimulatory molecules, and present antigen on MHC-I via both direct and cross-presentation. Whether LEC present to CD4 T cells on MHC-II is unknown. Interestingly, LEC express antigens otherwise restricted to a small number of peripheral tissues in an autoimmune regulatory element-independent manner. Direct presentation of peripheral tissue antigens (PTA) to CD8 T cells results in abortive proliferation and deletion, due to both a lack of costimulation and active PD-L1 engagement. Autoimmunity develops when deletion is subverted, suggesting that LEC presentation of PTA could lead to human disease if PD-1 signaling were impaired by genetic polymorphisms, or aberrant costimulation occurred during inflammation. The expression of additional inhibitory molecules, which are not involved in LEC-mediated deletion, suggests that LEC may have additional immunoregulatory roles. LEC express receptors for several immunomodulatory molecules whose engagement alters their phenotype and function. In this review we describe the role of LEC in distinct anatomical locations in controlling immune cell trafficking, as well as their emerging role in the regulation of T cell tolerance and immunity.
    Frontiers in Immunology 09/2012; 3:305. DOI:10.3389/fimmu.2012.00305
Show more