Lymph Node T Cell Homeostasis Relies on Steady State Homing of Dendritic Cells

Abstract

Little is known about mechanisms determining the homeostasis of lymphocytes within lymphoid organs. Applying different mouse models, including conditionally proficient Ccr7 gene-targeted mice, we now show that semimature steady state dendritic cells (sDCs) constitutively trafficking into lymph nodes (LNs) were essential contributors to T cell homeostasis in these organs. sDCs provided vascular endothelial growth factor known to support high endothelial venule formation, thus facilitating enhanced homing of T cells to LNs. The presence of sDCs led to increased CCL21 production in T-zone fibroblastic reticular cells. CCL21 is a ligand for CCR7 known to regulate homing as well as retention of T cells in LNs. In addition, we provide evidence that CCL21 binds to the surface of DCs via its heparin-binding domain, further explaining why T cells leave LNs more rapidly in the absence of sDCs. Together, these data reveal multiple roles for sDCs in regulating T cell homeostasis in LNs.

Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naïve CD4 + and CD8 + T cells

“…Access to SLOs impacts T-cell survival (39), and decreasing DC numbers reduces homing to SLOs through effects on chemokine signaling (40,41). Here we show that DCs can also influence T-cell LN transit times on the basis of interactions via MHCII.…”

ACKR4 on Stromal Cells Scavenges CCL19 To Enable CCR7-Dependent Trafficking of APCs from Inflamed Skin to Lymph Nodes

“…Some studies (23,26), but not others (21), also report a reduction in total LN cellularity in Ackr4-deficient mice at steady state. Because semimature DC modify high endothelial venules to increase lymphocyte recruitment to LN at steady state (9,10), it is perhaps not surprising that a strong and sustained mAPC migration defect in resting Ackr4-deficient mice is accompanied by a reduction in overall LN cellularity. The reduced abundance of LC and Langerin + dDC in the ILN of Ackr4-deficient mice in our colony is clearly not sufficient to cause this.…”

“…At steady state, there is a constant flux of these cells from skin to skin-draining lymph nodes (LN), and this cellular traffic is enhanced when the skin becomes infected or inflamed. This is profoundly dependent on mAPC expression of CCR7, a receptor for two chemokines, CCL19 and CCL21 (2)(3)(4)(5)(6)(7)(8)(9)(10). CCL19 is dispensable for the migration of CCR7 + mAPC from skin to LN (11,12).…”

Critical Role of Dendritic Cells in T Cell Retention in the Interfollicular Region of Peyer’s Patches

“…They showed that semimature DCs produce vascular endothelial growth factor, which induces the growth and differentiation of HEVs and efficient homing of T cells to LNs. They also showed that semimature DCs not only promote the production of CCL21 from stromal cells but also bind CCL21 via the heparin-binding domain (29). Our study demonstrated that HEVs developed normally in the cDC-depleted mice, and cDCs did not increase the expression of CCL21 from stromal cells, indicating that semimature DCs and cDCs regulate T cell distribution in different ways.…”

“…Additionally, unlike in our experiments, long-term treatment of CD11c-DTR mice with DT (∼8 d) was required to observe these phenotypes. Another study recently reported that semimature DCs reached LNs via the afferent lymph, which is also involved in the T cell homeostasis in the LN (29). They showed that semimature DCs produce vascular endothelial growth factor, which induces the growth and differentiation of HEVs and efficient homing of T cells to LNs.…”