CD4+ T cells must survey peripheral tissues of the body for damage or infection, a process that is critically dependent on rapid interstitial T cell migration. Although processes controlling T cell homing to and exit from the vasculature are well characterized, the mechanisms used by T cells for interstitial migration remain poorly defined. Initial studies characterizing T cell migration in lymph nodes and leukocyte migration in non-inflamed tissues indicate that cells utilize an integrin-independent mechanism for motility that is dependent on cytoskeletal forces to propel cells forward by pushing off of components of the extracellular matrix (ECM). However, inflamed tissues may not provide the required three-dimensional structure for this "biophysical" migration. Indeed, lab data suggest that in a strongly pro-inflammatory dermal environment, a decrease in ECM density was accompanied by a requirement for matrix-binding ?V?1?3 integrins for effective Th1 cell motility. However, in a model of skin inflammation, in which the ECM remains dense, Th1 cells do not have a similar requirement for integrins. We believe that the degree of confinement within the inflamed tissue dictates the mechanism used by T cells for movement. Additionally, we have observed that Th1 and Th2 cells exhibit different patterns of motility within the same inflamed tissue, raising the possibility of both inflammation- and cell-specific requirements for motility. This proposal seeks to define requirements for effector T cell interstitial migration, functional consequences of impaired migration, and to determine which factors may alter requirements for the movement of different CD4+ T cell subsets. We will first assess the mechanism used by Th1 cells for motility in several distinct inflammatory environments. Second, we will determine functional outcomes after impaired migration by measuring T-DC contacts, TCR signaling, and cytokine secretion as a readout of effector function. Finally, we will directly compare Th1 and Th2 cells to determine if observed differences in motility are due to cell-intrinsic or environmental factors. The goal of these studies is to dissect factors that drive and influence interstitial T cell migration, which my reveal targets for inflammation-specific or cell-specific immunomodulatory therapies that may mitigate distinct immune pathologies.
The movement of immune cells through inflamed tissues underlies the ability of these cells to locate areas of infection or damage and carry out effector function. However, the mechanisms that immune cells use for motility are poorly understood, and current medications that broadly block motility can have severe and unpredictable side effects. We aim to define requirements for migration in several types of inflammation and for distinct types of immune cell. The experiments proposed here have the potential to identify targets for the development of specific therapies to more safely treat inflammatory diseases.