Th1 cells are critical tissue organizers of myeloid-rich perivascular activation niches

Aggregating immune cells within perivascular niches (PVN) can regulate tissue immunity in infection, autoimmunity and cancer. How cells are assembled at PVNs and the activation signals imparted within remain unclear. Here, we integrate dynamic time-resolved in vivo imaging with a novel spatially-resolved platform for microanatomical interrogation of transcriptome, immune phenotype and inflammatory mediators in skin PVNs. We uncover a complex positive-feedback loop within CXCL10 ⁺ PVNs that regulates myeloid and Th1 cell positioning for exchange of critical signals for Th1 activation. Th1 cells spend ∼24h in the PVN, receiving initial peripheral activation signals, before redeploying to the inflamed dermal parenchyma. Niche-enriched, CCR2-dependent myeloid cells were critical for Th1 IFNγ-production. In turn, PVN instructional signals enabled Th1s to orchestrate PVN assembly by CXCR2-dependent intra-tissue myeloid cell aggregation. The results reveal a critical tissue organizing role for Th1s, gained rapidly on tissue entry, that could be exploited to boost regional immunity.

Perivascular niche (PVN): myeloid hubs in inflamed mouse and healthy human skinTh1 cells enter, get activated, and leave the PVN within first 24h of tissue entryAntigen-specific signals in the PVN promote the tissue organizing functions of Th1sTh1 cells assemble the PVN via CXCR2-dependent myeloid cell aggregation.