# Fibroblastic reticular cells direct the initiation of T cell responses via CD44

## TL;DR

This study shows that CD44 on fibroblastic reticular cells is crucial for T cell activation, and a virus protein disrupts this process to evade immunity.

## Contribution

The study identifies CD44 on fibroblastic reticular cells as a key regulator of T cell priming and reveals a novel stroma-based mechanism of antiviral immunity.

## Key findings

- The viral protein m11 inhibits antiviral immunity by targeting CD44 on fibroblastic reticular cells.
- m11 disrupts CD44 interactions with hyaluronic acid, impairing dendritic cell trafficking and T cell priming.
- CD44 is essential for the function of the fibroblastic reticular cell network in adaptive immune responses.

## Abstract

The movement of dendritic cells and T cells within secondary lymphoid organs is critical for the development of adaptive immune responses1,2. Central to this process is the fibroblastic reticular cell (FRC) network, which forms a highly organized conduit system that facilitates the movement of and interactions between dendritic cells and T cells3–6. Previous studies have partly characterized how FRCs support these interactions7,8. However, the molecular mechanisms that operate under physiological conditions remain unknown. Here we show that the viral protein m11, encoded by the herpesvirus murine cytomegalovirus (CMV), inhibits antiviral immunity by targeting the FRC network and interfering with a critical function of cellular CD44. We found that m11 binds to CD44 and established that m11 perturbs the molecular interactions of CD44 with its natural ligand, hyaluronic acid. The interaction of m11 with CD44 impairs the trafficking of dendritic cells within the spleen, thereby impeding efficient priming of naive T cells and the initiation of antiviral CD8 T cell responses. The targeting of CD44 by CMV reveals CD44 as a molecule that is essential to the functioning of the FRC network and uncovers a previously unrecognized stroma-based mechanism that is critical for the generation of effective T cell responses.

CD44 expressed by fibroblastic reticular cells in secondary lymphoid organs regulates trafficking of dendritic cells, and thus has an essential role in the priming of T cells and the adaptive immune response.