Perivascular Activation Niches
Despite a random pattern of T cell migration in the lymph node and peripheral tissues, T cell activation shows a high degree of spatial preference. We have identified a perivascular activation niche in the inflamed skin that links Th1 tissue entry with early activation.
How effector T cells find and interact with antigen presenting cells at sites of inflammation/infection is poorly understood. Most intravital imaging studies conclude that T cells scan inflamed tissues in a random non-directional fashion. But the range of tissue ‘searched’ by CD4+ T cell effectors and the frequency of APC encounter within inflamed tissues has not been determined. Therefore, how CD4+ T cells ultimately position themselves for effective anti-pathogen immunity remains elusive.
Using a chemokine reporter for the pro-inflammatory chemokines CXCL9 and CXCL10 to visualize the cellular source of chemokine production in the inflamed skin, we have identified spatially restricted perivascular activation niches (PACs) defined by chemokine producing cells enriched for MHC-IIhigh antigen presenting cells that direct the entry and point of activation of Th1 cells. Current studies seek to understand the immune cell types that shape the location and generation of the activation niche and to determine the functional consequences of T cell activation in these specialized microenvironments.
Our working hypotheses is that initial peripheral T cell activation occurs in chemokine-rich perivascular niches that serve to nucleate and amplify T cell activation early after tissue entry. We propose that activation in these perivascular niches licenses Th1 cells for efficient pathogen clearance. We are utilizing approaches for spatial, or niche, transcriptomics to determine how this novel activation hub modulates T cell function.
Prizant et al 2021 Cell Reports.
Bala, McGurk et al Immunological Reviews (in press)