Enhanced MHC Class-II Expression in Fibroblastic Reticular Cells Associates with Maturation.

Area of Science:

• Immunology
• Cell Biology
• Autoimmunity

Background:

• Peripheral tolerance, crucial for preventing autoimmunity, is maintained by fibroblastic reticular cells (FRCs) in lymph nodes.
• FRCs present self-antigens via major histocompatibility complex (MHC) class II, but the link between gene expression and protein levels for tolerance is unclear.
• FRC subsets exhibit distinct markers, functions, and locations within the lymph node microenvironment.

Purpose of the Study:

• To investigate the relationship between MHC class II gene expression and protein levels in murine fibroblastic reticular cells (FRCs).
• To identify specific FRC subsets involved in maintaining peripheral tolerance.
• To explore potential therapeutic targets for autoimmune diseases based on FRC characteristics.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of murine FRCs.
• Extracellular protein staining for MHC class II.
• Pseudotime trajectory analysis to assess gene expression dynamics.
• Validation in fresh lymph node cell suspensions from mice and humans.

Main Results:

• Murine T-zone reticular cells (TRCs) show the highest MHC class II transcript levels.
• MHC class II protein levels are elevated across multiple FRC subsets, not solely TRCs.
• Gene expression for MHC class II, BST1, and CD200 increases along a maturation trajectory, with TRCs at the end.
• MHC class II protein expression correlates with BST1+ FRCs in mice and BST1+CD200+ TRCs in humans.

Conclusions:

• Mature FRC subsets, characterized by BST1 expression and MHC class II protein presentation, are identified.
• These mature FRCs are crucial for maintaining peripheral tolerance.
• Targeting these specific FRC subsets may offer a novel therapeutic strategy for autoimmune diseases.