Mature dendritic cells orchestrate age-associated regulatory lymphoid niches in tissues

Ines Marin¹, Marcela Blanca Morales¹, Jessica Preston¹, Kevin Marroquin¹, Zhichang Yang¹, Ying Zhu¹, Joshua Webster_¹, Christine Moussion¹

¹Genentech, South San Francisco, California

Spontaneous ectopic lymphoid structures arise with aging and chronic tissue stress, yet the cellular mechanisms that initiate their formation and determine their function remain poorly understood. Here we identify tissue persistence of mature conventional dendritic cells (cDC) as a trigger of spontaneous ectopic lymphoid organization. In aged and chronically inflamed human and mice tissues, mature cDC were enriched within organized lymphoid aggregates. In mice, enrichment of mature cDC in tissues by selective impairment of cDC egress or by cDC expansion induced age-dependent de novo tertiary lymphoid structures (TLS)-like aggregates across multiple tissues in the absence of overt inflammatory pathology. Age-related tissue stress licenses niche initiation, whereas cDC persistence maintains established niches. In the colon, where mucosal lymphoid structures occur at baseline, cDC retention remodeled lymphoid niches toward a regulatory state enriched in tissue-adapted Tregs and promoted Treg-dependent protection from intestinal injury. Altogether, our work identifies tissue cDCs as organizers of spontaneous tissue lymphoid niches with regulatory potential in homeostatic settings that could be manipulated for therapy.