Time-resolved transcriptomics reveals new integrin dynamics upon T cell tissue entry 3198

Abstract Description Type 1 T helper (Th1) cells must navigate varied tissue landscapes to find sites of infection. To enter inflamed tissues, Th1 cells must traffic through the blood, traverse the vascular endothelium, then encounter a complex interstitial space containing many cell types and remodeled extracellular matrix. It remains unclear how Th1 cells choreograph their movement through these diverse microenvironments. We hypothesize that Th1 cells dynamically modulate the expression of surface receptors for movement and positioning across specific stages, from tissue entry to tissue exploration, for position-dependent delivery of effector function. We use the photoconvertible Kaede protein as an optogenetic tool to “timestamp” Th1 cells in vivo. This system allows cohorts of cells to be followed as they enter the inflamed skin. Combined RNAseq and flow cytometry approaches revealed a set of integrins (α1, α2, α4, αV, β1, β3) upregulated on Th1 cells prior to LN exit and as the cells entered the tissue. However, integrins α1, α2, and α4 were rapidly transcriptionally downregulated within 24h of tissue entry. In contrast, αVβ3 was maintained as cells remained in the tissue. These data suggest that a distinct set of integrins is utilized for tissue entry while others are used to traffic through skin or remain in tissue. The temporal sequence found in this work may identify novel targets for manipulating Th1 effector function in treatments for infection, inflammation, autoimmunity, and cancer. Funding Sources Supported by NIH/NIAID R37 AI072690 to DJF Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)