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

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.