Project 2: Regulation of Effector T Cell Migration within Inflamed Tissues (PI: Deborah Fowell, Co-PI: Jim Miller)
Fundamental to immune-mediated protection is the ability of leukocytes to survey barrier surfaces and quickly respond to infection or tissue damage. Signals from cytokines, chemokines and cells (immune and stromal) within the tissue provide critical cues for T cell migration at sites of inflammation, but the mechanics of T cell motility to these signals is poorly understood. Our overall goal is to define mechanistic control points for T cell surveillance within functionally distinct sites of inflammation. In the long-term, identification of diverse requirements for T cell function will lead to the selective therapeutic targeting of specific tissues or pathologies. Inflammation results in a change in both the architecture of the tissue as well as its composition. Using intravital multiphoton microscopy of inflamed tissues, we find that interstitial T cell motility in the inflamed skin is highly dependent on alpha-v integrin. Blockade or genetic knock-down of alpha-v halts T cell interstitial movement and also attenuates effector function.
We hypothesize that T cell-matrix interactions are critical for lymphocyte surveillance of the inflamed tissue for efficient location of APCs necessary for activation of effector function. The inflamed tissue is highly complex and the efficiency and mode of surveillance will likely differ with the local array of cytokines, chemokines and cellular infiltrate. We have identified two likely modifiers of T cell motility: 1) the microstructure of collagen fibers and 2) the effector lineage of the infiltrating CD4+ T cell. Aim 1. Role of av-integrins in effector T cell surveillance in the inflamed dermis. Aim 2. Modes of T cell motility in distinct inflammatory environments. Aim 3. Functionally distinct effector T cell activity in inflammation. Effector T cells function to eradicate pathogens but also contribute to immunopathologies. By identifying key parameters for T cell effector activity in the inflamed dermis we will inform new inflammation-specific therapies.