PI: Charlotte Vines, Ph.D., Assistant Professor, Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center

In response to invasion by foreign pathogens, naïve T cells home to the lymph node, to interact with antigen presenting cells and mediate the resultant immune response. Homing of naïve T cells from blood to lymphoid organs is regulated, in part, by activation of chemokine receptors by distinct chemokines found in the local environment. These activated chemokine receptors trigger signaling pathways that can lead to firm adhesion of T cells through the integrins, a family of heterodimeric, transmembrane, adhesion proteins. The distinct molecular events that are initiated at each of these steps are still being defined. We propose to examine the signaling pathways, which are initiated by chemokine binding to the CCR7 G protein-coupled receptor, that lead to cell adhesion via activation of the leukocyte functional antigen (LFA-1) integrins. CCR7 is activated by binding to two different endogenous ligands, CCL19 (MIP3β/ELC/Exodus-3) and CCL21 (6Ckine/SLC/TCA4/ Exodus-2), which are differentially expressed in secondary lymphoid tissues. Naïve T cells and certain populations of central memory cells (Tcm) employ the CCR7 chemokine receptor and LFA-1 to target T cells to secondary lymphoid compartments enabling their association with and priming by mature dendritic cells. Interestingly, T cells respond differently to CCL19 than they do to CCL21. While both ligands can mediate activation of G protein signaling and adhesion of T cells to LFA-1, only CCL19 promotes receptor phosphorylation/sensitization, and robust protein kinase C (PKC) activation. In contrast, CCL21 promotes PKC independent activation of the Rap1/RAPL ras family members, which increases the avidity (local increase in concentration) of LFA-1, and thereby up regulates adhesion to via LFA-1. Furthermore, while CCL19 enhances proliferation of NK cells, CCL21 can inhibit proliferation of certain myeloid progenitors. These observations suggest the molecular events triggered in response to the different ligands are distinct. This proposal will examine the signaling events involved in CCR7 mediated adhesion, proliferation and cell migration by its two ligands CCL19 and CCL21 and will lead to a better understanding of the molecular events that are required to recruit T-cells during an immune response.

This grant was made possible by NIH Grant Number P20 RR016443 from the COBRE program of the National Center for Research Resources.

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