Fibroblastic FLT3L supports lymph node dendritic cells in the interfollicular niche

Area of Science:

• Immunology
• Cell Biology
• Developmental Biology

Background:

• Dendritic cell (DC) homeostasis in secondary lymphoid organs (SLOs) is critical for immune surveillance.
• Fms-like tyrosine kinase 3 ligand (FLT3L) is a key cytokine for DC development and maintenance.
• The specific cellular source and niche of FLT3L within SLOs remain largely undefined.

Purpose of the Study:

• To identify the stromal cell source of FLT3L responsible for maintaining DC homeostasis in lymph nodes.
• To elucidate the mechanisms by which this source supports DC development, survival, and function.
• To investigate the impact of this FLT3L source on adaptive immune responses.

Main Methods:

• Utilized a novel genetic model to trace and manipulate Gremlin1 (GREM1)-expressing cells.
• Employed spatial transcriptomics and cytofluorometry for cellular localization and molecular analysis.
• Assessed T cell responses following immunization and infection in genetically modified models.

Main Results:

• Identified GREM1-expressing fibroblastic reticular cells (FRCs) as the primary source of FLT3L in lymph nodes.
• Demonstrated that GREM1+ FRC-derived FLT3L supports the proliferation and survival of DC precursors (preDCs) and conventional DCs (cDCs).
• Showed that loss of GREM1+ FRC-derived FLT3L impairs DC activation and subsequent T cell responses to antigens.

Conclusions:

• GREM1+ FRCs constitute a critical stromal niche supporting DC homeostasis and function in lymph nodes.
• FLT3L produced by GREM1+ FRCs is essential for maintaining preDC and cDC populations within the interfollicular zone.
• These findings reveal a key mechanism of stromal cell regulation of DC populations and adaptive immunity.