Poster Presentation 18th International Symposium on Dendritic Cells 2026

Dissecting the development and function of PRDM16+ tolerogenic dendritic cells (#216)

Liuhui Fu 1 , Dan R Littman 1 2
  1. NYU Langone Health, Manhattan, NY, United States
  2. Howard Hughes Medical Institute, NY, United States

The intestinal immune system must maintain tolerance to harmless dietary and microbial antigens while preserving protective immunity against pathogens. Peripherally induced regulatory T (pTreg) cells play a pivotal role in mediating this tolerance. We recently identified PRDM16⁺ tolerogenic dendritic cells (tolDCs) as a distinct antigen-presenting cell population required for the differentiation of both food- and microbiota-specific pTreg cells. Using multiple genetic models, we found that disruption of the tolerogenic DCs through deletion of Prdm16, Rorc(t), or the Rorc(t)+7 kb cis-regulatory element resulted in microbiota-specific proinflammatory T cell responses and a breakdown of oral tolerance, rendering animals susceptible to allergic inflammation. We next investigated the developmental origin and persistence of this population. PRDM16+ tolDCs were labeled by both Il7r- and Csf1r-based fate-mapping approaches, and disruption of either pathway alone was insufficient to eliminate their development or function. Notably, PRDM16+ tolDC development and function were independent of common γ chain signaling. Furthermore, inducible depletion of PRDM16+ tolDCs in adult mice abolished the generation of food antigen-specific pTreg cells. The PRDM16+ tolDC population subsequently recovered, together with its capacity to induce pTreg cell differentiation. To selectively label PRDM16+ tolDCs in vivo, we generated a Prdm16/Rorc(t) intersectional reporter mouse, providing a new genetic tool for investigating this specialized DC population. Together, these findings establish PRDM16+ tolDCs as a central regulator of intestinal immune tolerance and provide new insights into their development and maintenance.