Lymph node stromal cells: cartographers of the immune system

Abstract

econdary lymphoid organs (SLOs), including lymph nodes (LNs), spleen and Peyer's patches (PPs), serve as the body's sites of immune cell surveillance. SLOs provide the infrastructure to maintain immune homeostasis and facilitate rapid and effective immune responses. While spleen and PPs serve to filter material in the blood and gastrointestinal tract, respectively, LNs are strategically situated in proximity to lymphatic and vascular branching points to effectively filter antigens and facilitate immune cell entry from surrounding tissues. Pioneering studies of human lymphoid organ development from the 1970s revealed that humans possess hundreds of lymph nodes variably positioned throughout the body, whereas mice have 22 LNs that always develop in the same distinct body sites 1-3. The hallmark feature of SLOs is the highly ordered compartmentalization of T cells, B cells and myeloid cells to generate optimal antigen-specific adaptive immune responses. Non-hematopoietic lymph node stromal cells (LNSCs), made up of both mesenchymal and endothelial cells, are paramount to maintaining LN integrity and function. LNSCs play a key role in LN organogenesis, maintenance of LN cellularity and compartmentalization and supporting immune responses. In this review, we will address recent advances elucidating the contribution of LNSCs, primarily mesenchymal cells, during immune system development and immune responses in adulthood, and highlight ongoing work that aims to expand our understanding of the heterogeneity that exists among LNSCs. LNSC coordination of LN organogenesis LN organogenesis begins as early as embryonic day (E)12.5-E13.5 in mice and weeks 8-11 of gestation in humans via the interactions of two key cell types, lymphoid tissue inducer (LTi) cells and lymphoid tissue organizer (LTo) cells, which, when brought together, form the primordial LN anlagen 1,4. LTi cells, belonging to the family of innate lymphoid cells (ILCs), originate from hematopoietic CD45 + Lin-IL-7Rα + Sca1 lo c-Kit lo common lymphoid progenitors (CLPs) in the mouse fetal liver and differentiate via expression of the transcription factors Id2 and RORγt. Mice deficient in Id2 or Rorγt are devoid of LTi cells and consequently lack LNs, highlighting the importance of LTi cells in this process 5,6. Differentiated LTi cells, also categorized as group 3 ILCs, are CD45 + CD3-RORγt + cells and are further defined by their expression of IL-7Rα, integrin α4β7, receptor activator of NF-κB (RANK) and its ligand RANKL, lymphotoxin-α1β2 (LT)

Intrinsic defects in lymph node stromal cells underpin poor germinal center responses during aging

“…Stromal cells are critical to lymph node structure, dictating the T and B cell areas and directly regulating immune cell homeostasis and adaptive immune responses 12,13,14 . Stromal cells form the physical scaffold upon which immune cells migrate and produce molecules that dictate the migration and survival of immune cells 15,16,17 .…”

Human Lymphoid Stromal Cells Contribute to Polarization of Follicular T Cells Into IL-4 Secreting Cells

“…Having identified two subsets of human CXCR5 + CD4 + follicular T cells based on their differential expression of CXCR5 and PD-1 ( Supplemental Figure 1 ), we decided to explore the impact of FRCs on both GC-Tfh and R5-PD1 dim cells. Indeed, FRCs express high levels of adhesion molecules, extracellular matrix components, and LN chemokines, and promote B and T cell recruitment, adhesion, and survival ( 7 , 21 , 22 ) in both T-cell zone, inter-follicular area, and at follicle border, the place of T-cell priming for Tfh differentiation. In addition, FRCLs obtained by in vitro differentiation of uncommitted TSCs have been proposed as a good model to perform functional FRC evaluation ( 16 , 23 ).…”

Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer

“…Some preclinical findings have been made that can guide such further studies. Lymph node biology studies suggest important roles for FAP-positive mesenchymal cells in controlling the migration and compartmentalization of T cells [26]. Studies in mouse cancer models have also shown that the extracellular matrix make-up, controlled by fibroblasts, can affect intra-tumoral immune cell migration [43].…”

“…Moreover, FAP expression by stromal cells can have a profound indirect effect on the immune compartment of tumors promoting a shift in T-cell phenotypes towards T-regulatory cells [23]. Interestingly, studies on immune-regulatory mesenchymal fibroblast-like cells of lymph nodes suggest that these cells are derived from FAP+ precursor cells [26,27].…”