Highlights d CXCL10 expression is limited to discrete perivascular niches in the inflamed skin d The CXCL10 + niches are hotspots or preferred sites of Th1 tissue entry d The niche is enriched for MHC-II + moDCs and supports prolonged Th1:APC interactions d IFNg enhances niche availability, boosting opportunities for Th1:APC encounter

Exposure to the pesticide paraquat (PQ) increases the risk of Parkinson’s disease (PD), and its effect may be modulated by genetic or other environmental factors. The neuropeptide PACAP (pituitary adenylyl cyclase activating polypeptide, Adcyap1) has been shown to enhance tyrosine hydroxylase (TH) and VMAT2 expression, protect dopaminergic (DA) neurons against the neurotoxin 6-hydroxydopamine, regulate neuronal mitochondria, and inhibit inflammation. Decreased expression of PACAP may thus interact with environmental factors such as PQ to increase the risk of PD. To mimic a low level environmental exposure to PQ, wild type (WT) and PACAP knockout (KO) mice were given a single [10 mg/kg] dose of PQ, a regimen that did not induce loss of TH expression or DA neurons in WT mice. This treatment reduced the number of TH-positive cell bodies in the substantia nigra pars compacta (SNpc) of PACAP KO. Because inflammation is also a risk factor for PD, we performed a quantitative analysis of SNpc Iba+ microglia. As expected, PQ increased the number of larger microglial profiles, indicative of activation, in WT mice. Strikingly, microglial activation was already evident in PACAP KO mice in the basal state. PQ caused no further activation in these mice, although TNF-α gene expression was enhanced. In the periphery, PQ had no effects on the abundance of proinflammatory Th1 or Th17 cells in WT mice, but increased the numbers of anti-inflammatory regulator T cells (Tregs). PACAP KO mice, in contrast, had elevated numbers of Th17 cells after PQ, and the induction of Tregs was impaired. The results indicate that endogenous PACAP acts to maintain the integrity of dopaminergic neurons during exposure to PQ, an action that may be linked to its ability to regulate microglia and/or other immune cells.

Successful immunity to infection, malignancy, and tissue damage requires the coordinated recruitment of numerous immune cell subsets to target tissues. Once within the target tissue, effector T cells rely on local chemotactic cues and structural cues from the tissue matrix to navigate the tissue, interact with antigen‐presenting cells, and release effector cytokines. This highly dynamic process has been “caught on camera” in situ by intravital multiphoton imaging. Initial studies revealed a surprising randomness to the pattern of T cell migration through inflamed tissues, behavior thought to facilitate chance encounters with rare antigen‐bearing cells. Subsequent tissue‐wide visualization has uncovered a high degree of spatial preference when it comes to T cell activation. Here, we discuss the basic tenants of a successful effector T cell activation niche, taking cues from the dynamics of Tfh positioning in the lymph node germinal center. In peripheral tissues, steady‐state microanatomical organization may direct the location of “pop‐up” de novo activation niches, often observed as perivascular clusters, that support early effector T cell activation. These perivascular activation niches appear to be regulated by site‐specific chemokines that coordinate the recruitment of dendritic cells and other innate cells for local T cell activation, survival, and optimized effector function.