Fibroblastic reticular cells: organization and regulation of the T lymphocyte life cycle

Abstract

The connective tissue of any organ in the body is generally referred to as stroma. This complex network is commonly composed of leukocytes, extracellular matrix components, mesenchymal cells, and a collection of nerves, blood, and lymphoid vessels. Once viewed primarily as a structural entity, stromal cells of mesenchymal origin are now being intensely examined for their ability to directly regulate various components of immune cell function. There is particular interest in the ability of stromal cells to influence the homeostasis, activation, and proliferation of T lymphocytes. One example of this regulation occurs in the lymph node, where fibroblastic reticular cells support the maintenance of naive T cells, induce Ag-specific tolerance, and restrict the expansion of newly activated T cells. In an effort to highlight the varied immunoregulatory properties of fibroblastic reticular cells, we reviewed the most recent advances in this field and provide some insights into potential future directions.

Figure 1

LN FRCs regulate several aspects of the T cell life cycle. |A| FRCs facilitate lymphocyte arrival and organization in the LN. FRC-derived chemokines CCL19 and CCL21 support naïve T cell trafficking across HEVs and retains T cells in the LN paracortex through their ligation to CCR7. |B| T cell survival is maintained by FRCs. FRC-derived IL-7 supports the survival and homeostasis of naïve T cells that reach the T cell zone. |C| FRCs facilitate the interactions between antigen-presenting dendritic cells and T cells. The trafficking of migratory DCs to the LN is induced by the ligation between the CCR7 receptor on DCs and FRC-derived chemokines CCL19 and CCL21. Upon arrival in the LN, DC migration along the FRC network requires the engagement of DC-expressed CLEC-2 to gp38 on FRCs. Disruption of this signaling axis ultimately leads to reduced T cell priming. |D| FRCs induce T cell tolerance via the expression of peripheral tissue-restricted antigens. Upon antigen presentation, FRCs induce deletional tolerance of MHC class I-restricted CD8⁺ T cells and hyporesponsiveness of MHC II-restricted CD4⁺ T cells. |E| FRCs restrict the expansion of newly activated T cells. Activated T cells release IFN-γ and TNF-α, which act synergistically to endow FRCs with suppressive capabilities, mediated through the activity of nitric oxide. This suppression occurs in an antigen-independent fashion, which may ultimately be required to protect the organ from excessive swelling and damage during ongoing immune responses. |F| FRCs influence the maintenance of memory precursor effector cells. Ablation of FRCs during the late phase of an immune response leads to a modest reduction in the percentage of memory precursor effector cells. The mechanism controlling this reduction has not been determined although FRC-derived IL-7 and IL-15 are hypothesized to be involved.