A Distinct Subset of Fibroblastic Stromal Cells Constitutes the Cortex-Medulla Boundary Subcompartment of the Lymph Node

Abstract

The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRβ, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different from CXCL12highLepRhigh FSCs in the medullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN.

Lymph node fibroblastic reticular cells steer immune responses

“…The T cell zone (T-zone) is filled with T-zone reticular cells (TRCs). The deep cortex periphery (DCP) reticular cells (DRCs) fill the DCP [ 5 ] and the medullary reticular cells (MedRCs) form a dense network in the mouse LN medulla [ 2 , 6 ]. Murine FRC subsets originate from embryonic fibroblast activation protein-α (FAP) + mesenchymal lymphoid tissue organizer (LTo) cells (see Glossary ) [ 7 , 8 ], although the mechanisms directing the differentiation into different FRC lineages are not well known.…”

“…The T cell zone (T-zone) reticular cells (TRCs) form the network supporting the T-zone [ 6 ]. The deep cortex periphery reticular cells (DRCs) fill the deep cortex periphery (DCP) [ 5 ]. The medullary reticular cells (MedRCs) form a dense network in the medulla [ 2 , 6 ].…”

“…Form a dense irregular network in the DCP region by highly expressing desmin, ER-TR7, PDGFRβ, CCL19, and CXCL12 [ 5 ]…”

Differentiation and activation of fibroblastic reticular cells

“…Over the last 10 years, several strains of reporter mice and lineage tracing models expressing Cre recombinase and/or fluorescent proteins (eg, the enhanced yellow fluorescent protein, EYFP) under the promoter of key FRC signature genes have been developed, revolutionizing FRC immunobiology (Table 1). Two such transgenic mouse models that take advantage of FRC chemokine expression are the Ccl19-Cre 24 (lymph node at embryonic day (E) 16.5, 24 Peyer's patch at E18.5, 27 spleen at E19.5 23 ) thereby targeting FRCs in lymph nodes, 21,24,28 the splenic white pulp, 29 and Peyer's patches. 30 Similarly, in lymph node anlagen, the Cxcl13-Cre transgene is expressed at E14 in mesenchymal stromal cells, marking all major lymph node FRC subsets in adult mice.…”

“…The two TBRC subsets share an overlapping expression of genes encoding CXCL13 and CCL19, however, the marker gene profile of one subset more closely resembles that of Ccl19 high TRCs and the second of MedRCs. It remains unclear whether these gene signatures reflect gradual differences in TBRCs lining B cell follicles distributed more closely to the medulla or a subset in the lymph node cortex 21 . Although TBRCs have not yet been described in the splenic white pulp, a recent study of Peyer's patch FRCs also described a TBRC subset sharing a similar molecular profile and spatial localization as those described in lymph nodes 27 …”