Chemokine-dependent migration of lymphocytes and dendritic cells (DCs) into specific anatomic compartments is essential to optimal T cell immune responses against foreign pathogens. The p110? isoform of the phosphatidyolinositol 3-kinase (PI 3-K) family of lipid kinases is activated by chemokine receptors and other G protein coupled receptors. Lipid products produced by PI 3-K are essential in forming polarized morphologies necessary for directional cell migration and PI 3-K can regulate chemokine-dependent integrin activation. Neutrophils and macrophages from mice deficient in poly exhibit impaired migration to multiple chemotactic stimuli. While p110gamma -/- mice also exhibit impaired CDS T cell anti-viral responses and CD4 T cell-dependent antibody responses, naive T cell migration both in vitro and in vivo is not dependent on p110gamma. However, migration of p110gamma -/- effector T cells into inflammatory sites is dramatically impaired, and p110gamma -/- mice have reduced numbers of DCs in secondary lymphoid organs. Thus, we propose that p110gamma regulates T cell immune responses by specifically regulating DC trafficking into secondary lymphoid organs that is critical for naive T cell priming, and the subsequent migration of effector T cells into inflammatory sites.
In Aim 1, we will define the role that p110gamma plays in chemokine-dependent integrin activation and cell polarization on effector T cells.
In Aim 2, we will utilize adoptive transfer approaches with wild-type and p110gamma -/- mice to determine the function of p110gamma on CD4 T cell activation in vivo, chemokine-dependent migration of activated T cells in lymph nodes and into non-lymphoid tissue, and DC trafficking and function.
In Aim 3, we will define the role of p110gamma in regulating the activation and migration of CDS T cells in response to vaccinia virus. These studies will provide important new insights into the mechanism by which p110gamma regulates T cell-specific immune responses via regulation of T cell and DC migration. Defining the function of p110gamma in regulating homeostatic versus inflammatory trafficking in vivo is critical to the potential utility of p110gamma as an anti-inflammatory drug target. Finally, these studies will provide new insights into T cell responses to vaccinia, which will be critical to the development of more effective smallpox vaccines that have fewer adverse effects.
| Denucci, Christopher C; Mitchell, Jason S; Shimizu, Yoji (2009) Integrin function in T-cell homing to lymphoid and nonlymphoid sites: getting there and staying there. Crit Rev Immunol 29:87-109 |
| Thomas, Molly S; Mitchell, Jason S; DeNucci, Christopher C et al. (2008) The p110gamma isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites. J Leukoc Biol 84:814-23 |
| Martin, Amanda L; Schwartz, Matthew D; Jameson, Stephen C et al. (2008) Selective regulation of CD8 effector T cell migration by the p110 gamma isoform of phosphatidylinositol 3-kinase. J Immunol 180:2081-8 |
