Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 ⁺ T cells

Abstract

Fibroblastic reticular cells (FRCs), through their expression of CC chemokine ligand (CCL)19 and CCL21, attract and retain T cells in lymph nodes (LNs), but whether this function applies to both resting and activated T cells has not been examined. Here we describe a model for conditionally depleting FRCs from LNs based on their expression of the diphtheria toxin receptor (DTR) directed by the gene encoding fibroblast activation protein-α (FAP). As expected, depleting FAP + FRCs causes the loss of naïve T cells, B cells, and dendritic cells from LNs, and this loss decreases the magnitude of the B-and T-cell responses to a subsequent infection with influenza A virus. In contrast, depleting FAP + FRCs during an ongoing influenza infection does not diminish the number or continued response of activated T and B cells in the draining LNs, despite still resulting in the loss of naïve T cells. Therefore, different rules govern the LN trafficking of resting and activated T cells; once a T cell is engaged in antigen-specific clonal expansion, its retention no longer depends on FRCs or their chemokines, CCL19 and CCL21. Our findings suggest that activated T cells remain in the LN because they down-regulate the expression of the sphingosine-1 phosphate receptor-1, which mediates the exit of lymphocytes from secondary lymphoid organs. Therefore, LN retention of naïve lymphocytes and the initiation of an immune response depend on FRCs, but is an FRC independent and possibly cell-autonomous response of activated T cells, which allows the magnitude of clonal expansion to determine LN egress. viral infection | T-cell migration | lymph node stroma

Fibroblastic Reticular Cells: Organization and Regulation of the T Lymphocyte Life Cycle

“…A recent report by Denton et al (59) provided some validation to this hypothesis by showing a modest reduction in MPEC percentages following FRC depletion during the late phase of an ongoing influenza virus infection. Interestingly, FRC ablation reduced the percentage of MPECs without negatively impacting the abundance of short lived effector cells (59). Selective reduction of MPECs likely occurred in response to decreased FRC-derived IL-7, which is known to support MPEC formation (60) (Fig.…”

T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection

“…Moreover, once T cells are activated, they down-regulate LN retention signals such as CCR7 and thus are primed to egress from the reactive LN and mobilize into the circulation. Interestingly, a study recently demonstrated that naive and effector T cells respond to CCR7 cues differently (32). When CCL19-and CCL21-expressing fibroblastic reticular cells (FRCs) were conditionally depleted, it resulted in the loss of naive, but not effector, T cells from the LN.…”

“…When CCL19-and CCL21-expressing fibroblastic reticular cells (FRCs) were conditionally depleted, it resulted in the loss of naive, but not effector, T cells from the LN. The authors (32) suggested that reduced expression of S1PR1, rather than CCR7 signaling, influenced the retention of antigen-specific T cells until they were ready to leave the LN. Therefore, we asked the important question: In light of the infection-induced inflammatory environment, are effector T cells that lack retention signals and are poised to exit the dLN dependent on S1PR1 for egress after a local viral infection?…”

Stromal Cells in Chronic Inflammation and Tertiary Lymphoid Organ Formation

“…Fearon's group (212) has elegantly shown that conditional deletion of Pdpn + FAP + FRCs in the early (but not established) phases of the response to influenza severely compromises the CD8-mediated host response. Similarly, deletion of LTβR in lymph node FRCs results in impaired immune responses to viral infections (131,213).…”