# Enhanced MHC Class‐II Expression in Fibroblastic Reticular Cells Associates with Maturation

## TL;DR

Fibroblastic reticular cells in lymph nodes help prevent autoimmunity by expressing MHC class-II proteins, with mature subsets like BST1+CD200+ cells playing a key role.

## Contribution

Identification of BST1+CD200+ fibroblastic reticular cells as a mature subset with high MHC class-II expression in mice and humans.

## Key findings

- Murine T-zone fibroblastic reticular cells (TRCs) have the highest MHC class-II transcript levels.
- MHC class-II protein expression is elevated in multiple fibroblastic reticular cell subsets.
- BST1+ fibroblastic reticular cells in mice and BST1+CD200+ TRCs in humans show high MHC class-II expression.

## Abstract

Autoimmunity can be initiated by autoreactive T cells that escaped central and peripheral tolerance induction. Peripheral tolerance in lymph nodes (LNs) is maintained by fibroblastic reticular cells (FRCs) via self‐antigen presentation in major histocompatibility complex (MHC) class II. FRCs can be divided into various subsets, with specific markers, functions, and locations. FRCs located in the T‐cell zone (TRCs) can express genes for antigen presentation in MHC class‐II, for example, H2‐Ab1 and Cd74, as well as the immune inhibitory ligand Cd200. However, whether this can be linked to MHC class‐II protein expression and thus tolerance is unknown. By combining scRNAseq on murine FRCs with protein staining for extracellular MHC class‐II, we confirm that murine TRCs have the highest MHC class‐II transcript levels, while protein levels are elevated in multiple FRC subsets. Gene expression for MHC class‐II, as well as Bst1 and Cd200, gradually increases along the pseudotime trajectory, with TRCs representing the end, indicating maturation. Finally, we validated in fresh LN cell suspensions that MHC class‐II protein expression is associated with murine BST1+ FRCs, independent of CD200, and with human BST1+CD200+ TRCs. This mature FRC subset, equipped to maintain peripheral tolerance, could be an interesting target for therapies against autoimmune diseases.

Fibroblastic reticular cells (FRCs) in lymph nodes contribute to peripheral tolerance via MHC‐class‐II‐mediated antigen presentation. Using scRNAseq and protein analysis, we identify BST1+CD200+ FRCs, including the mature T cell‐zone FRCs, as key MHC‐class‐II expressing subsets in mice and humans, highlighting their potential role in immune regulation.