CXCL10+ peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter

Correct positioning of T cells within infected tissues is critical for T cell activation and pathogen control. Upon tissue entry, effector T cells must efficiently locate antigen-presenting cells (APC) for peripheral activation. We reveal that tissue entry and initial peripheral activation of Th1 effector T cells are tightly linked to perivascular positioning of chemokine-expressing APCs. Dermal inflammation induces tissue-wide de novo generation of discrete perivascular CXCL10+ cell clusters, enriched for CD11c+MHC-II+ monocyte-derived dendritic cells. These chemokine clusters are “hotspots” for both Th1 extravasation and activation in the inflamed skin. CXCR3-dependent Th1 localization to the cluster micro-environment prolongs T-APC interactions and boosts function. Both the frequency and range of these clusters are enhanced via a T helper 1 (Th1)-intrinsic, interferon-gamma (IFNγ)-dependent positive-feedback loop. Thus, the perivascular CXCL10+ clusters act as initial peripheral activation niches, optimizing controlled activation broadly throughout the tissue by coupling Th1 tissue entry with enhanced opportunities for Th1-APC encounter. [Display omitted] •CXCL10 expression is limited to discrete perivascular niches in the inflamed skin•The CXCL10+ niches are hotspots or preferred sites of Th1 tissue entry•The niche is enriched for MHC-II+ moDCs and supports prolonged Th1:APC interactions•IFNγ enhances niche availability, boosting opportunities for Th1:APC encounter Prizant et. al. identify a perivascular peripheral activation niche for T cells, defined by myeloid cell expression of the chemokine CXCL10. These CXCL10+ perivascular clusters serve as hotspots for T cell entry into the inflamed skin and a niche for early activation.