# Sequential Lymphotoxin Beta Receptor and Retinoic Acid Receptor signals regulate cDC2 fates

## TL;DR

The study reveals how signals from two receptors guide the development of different types of dendritic cells in the spleen.

## Contribution

The study identifies sequential signals from Lymphotoxin Beta Receptor and Retinoic Acid Receptor that regulate cDC2 fates in mice.

## Key findings

- cDC2s arise from a CLEC9A+ progenitor and include T-bet+ cDC2A and two cDC2B subsets.
- RA signaling is required for cDC2A differentiation via Notch signals in the spleen.
- Lymphotoxin beta receptor signaling limits F-actin content to retain cDC2s in retinol delivery sites.

## Abstract

Type II conventional dendritic cells (cDC2) are functionally and phenotypically heterogenous. Previous work in mice and humans identified two cDC2 subsets (cDC2A and cDC2B) and a monocytic DC3 subset. However, the microenvironmental cues governing their distinct differentiation pathways remain unclear. Here we delineate murine cDC2 lineage relationships and the sequential signals required for cDC2A maintenance. We show that cDC2s, arising from the CLEC9A+ cDC progenitor, encompass T-bet-expressing cDC2A and two cDC2B subsets distinguished by MGL2 expression, with monocytic DC3 exhibiting transcriptional overlap with Mgl2− cDC2B. Among these subsets, T-bet+ cDC2A dominate the spleen where they require cell-intrinsic retinoic acid (RA) signaling to sustain their differentiation via Notch signals. Lymphotoxin beta receptor signaling on splenic cDC2s limits F-actin content retaining cDC2 at sites of retinol delivery. In summary, these data establish the developmental and transcriptional relationships between diverse cDC2 subsets and identify signals that regulate their prevalence in specific lymphoid tissues.