SIRPα⁺ dendritic cells promote the development of fibroblastic reticular cells in murine peripheral lymph nodes

Abstract

Nonhematopoietic stromal cells contribute to the organization and homeostasis of secondary lymphoid organs by producing cytokines and chemokines. The development and maintenance of these stromal cells are thought to be regulated by innate immune cells. Indeed, we recently showed that signal regulatory protein α (SIRPα)-positive dendritic cells (DCs) are essential for the proliferation and survival of podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) in mouse spleen. We have now established an in vitro culture system for lymph node stromal cells (LNSCs) isolated from mouse peripheral LNs. Activated DCs and TNF-α each promoted the proliferation of cultured LNSCs, most of which were found to be Pdpn + FRCs. Furthermore, ablation of SIRPα in CD11c + cells attenuated this effect of DCs on LNSC proliferation. Transplantation of activated DCs together with cultured LNSCs into the renal subcapsular space markedly increased the number of ER-TR7 + stromal cells as well as induced the accumulation of T cells and increased the expression of Ccl19 in the transplants. Ablation of SIRPα in CD11c + cells greatly impaired the development of LN-like structure in the transplants. Our findings thus suggest that SIRPα + DCs are important for the proliferation and differentiation of Pdpn + FRCs in peripheral LNs.Keywords: Dendritic cell r Fibroblastic reticular cell r Lymph node r SIRPα r Stromal cell Additional supporting information may be found online in the Supporting Information section at the end of the article.

Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin α4

“…The CLEC-2/Pdpn signaling axis also controls conduit matrix composition (30), suggesting that DCs contribute to the FRC-sheathed conduit system. In addition, signal regulatory protein α + cDCs support the proliferation and survival of FRCs in mouse spleen and LNs through the tumor necrosis factor αa signaling pathway (55,56). In turn, FRCs also sustain DCs, as shown by Kapoor et al, who identified a Grem1 + FRC subset that colocalizes with cDCs in paracortical regions and maintains the homeostasis of lymphoid tissue-resident cDCs (57).…”

FRC transplantation restores lymph node conduit defects in laminin α4–deficient mice

“…Immune cells in turn regulate FRC proliferation. For example, T cells and DCs can stimulate FRC expansion through LTβR signaling ( 32 , 33 ), and DCs promote proliferation of FRCs through signal regulatory protein α ( 34 ). In experimental autoimmune encephalomyelitis and colitis, T cell–derived IL-17 promotes FRC proliferation by enhancing their metabolic fitness.…”

Early immunomodulatory program triggered by pro-tolerogenicBifidobacterium pseudolongumdrives cardiac transplant outcomes

“…Chyou et al [68] and Kumar et al [69] showed the importance of DCs in regulating the structure of LN vasculature and stromal cells in response to and resolution of immune responses. Matozaki and colleagues identified important roles for SIRPa+ DCs in determining the growth and differentiation of LN stromal fibroblastic reticular cells (FRC) [70,71]. FRCs in turn are responsible for constructing the laminin a-chain scaffold that promotes immunogenic or tolerogenic niches within the LN to regulate immune responses [72][73][74].…”

“…Chyou et al 47 and Kumar et al 48 showed the importance of DCs in regulating the structure of LN vasculature and stromal cells in response to and resolution of immune responses. Matozaki and colleagues identified important roles for SIRPα+ DCs in determining the growth and differentiation of LN stromal fibroblastic reticular cells (FRC) 49,50 .…”