A Single-Cell Transcriptional Roadmap of the Mouse and Human Lymph Node Lymphatic Vasculature

Abstract

Xiang et al. scRNA-seq of Lymph Node Lymphatic Vasculature HIGHLIGHTS Computational alignments ("trajectories") predict LN LEC organization in situ, revealing a continuum of phenotypes punctuated by specialized clusters. Multiple intermediate phenotypes suggest LEC malleability. Gene profiles define niche-specific functional specialization. Medullary sinus LECs are comprised of Ptx3-LECs and Marco-LECs.-Distinct mechanisms for pathogen interactions and matrix modeling.-Ptx3-LECs: paracortical and central medullary sinuses near hilus; enriched for genes driving lymphangiogenic responses and lymphocyte egress.-Marco-LECs: peri-follicular medullary sinuses; macrophageassociated genes, complement and coagulation cascade. Niche-specific responses to inflammation.-IFN gene responses in SCS floor and medullary sinus LECs.-Suppression of LEC identity genes in responding subsets. Conserved and unique LEC subsets and gene programs across species.-Core subsets common to mouse and human.-Greater diversity of subsets and intermediates in human LN LECs.

In Sickness and in Health: The Immunological Roles of the Lymphatic System

“…There are also two transitional populations: bridge cells, linking ceiling LECs and floor LECS, and transitional zone LECs, between floor LECs and Marco-LECs. ACKR4 + ceiling LECs are most similar to valve cells, expressing extracellular matrix components and proteins to maintain cell-cell contacts [136,130]. ACKR4 itself is an atypical chemokine receptor, playing a vital role in regulating entry of CCR7 + DCs to the lymph node by scavenging CCR7 ligands from the sinus lumen and creating functional CCL21 gradients across the SCS floor [129].…”

“…Ptx3-LEC express LYVE-1, which is a widely used lymphatic marker [142] and has been shown to promote DC entry to lymphatic vessels in mouse dermis [91], discussed later in this review. Macrophage mannose receptor MR is also expressed both in peripheral LECs and Ptx-LECs, orchestrating lymphocyte egress from tissues through interacting with the leukocyte receptor CD44 [88], as well as binding microbes and pro- ACKR4 + ceiling LECs are most similar to valve cells, expressing extracellular matrix components and proteins to maintain cell-cell contacts [130,136]. ACKR4 itself is an atypical chemokine receptor, playing a vital role in regulating entry of CCR7 + DCs to the lymph node by scavenging CCR7 ligands from the sinus lumen and creating functional CCL21 gradients across the SCS floor [129].…”

“…LECs within the lymph node do not serve merely as conduit lining but rather are responsible for modulating adaptive immune responses, through antigen capture, presentation and archiving, as well as maintaining tolerance [ 135 ]. Recent gene profiling has revealed niche-specific functional specialization and specific markers of LECs within the lymph node, core subsets of which are common to both mouse and human [ 130 , 136 ]. These five main subsets include Foxc2 + valve LECs, Ackr4 + SCS ceiling LECs, Ccl20 + SCS floor LECs, Marco-LECs and Ptx3-LECs ( Figure 3 ).…”

“…ACKR4 itself is an atypical chemokine receptor, playing a vital role in regulating entry of CCR7 + DCs to the lymph node by scavenging CCR7 ligands from the sinus lumen and creating functional CCL21 gradients across the SCS floor [ 129 ]. Floor LECs appear more immunologically active, expressing transcripts for adhesion molecules (ICAM-1, VCAM-1, Glycam1, MAdCAM1) and chemokines (CCL20, CXCL4, CXCL1) suggestive of roles in leukocyte migration, as well as immune cell function modulators (CXCL4, CSF1, BMP2/SMAD), MHC class II presentation (CD74, H2-Ab1) and tolerance (PDL1) [ 130 , 136 , 137 ]. Lymph from the SCS then passes through medullary sinuses, coming into contact with Marco-LECs.…”

“…Gene expression in Ptx3-LECs is most similar to that of LECs from peripheral tissues (although Ptx3 itself is not reported to be highly expressed in peripheral LECs) and both share certain morphological features, including blind ends specialized for fluid uptake [ 60 , 136 , 140 , 141 ]. Ptx3-LEC express LYVE-1, which is a widely used lymphatic marker [ 142 ] and has been shown to promote DC entry to lymphatic vessels in mouse dermis [ 91 ], discussed later in this review.…”