Chemokines are a superfamily of secreted chemotactic proteins which play a critical role in host immune surveillance and defense by directing leukocyte migration. The sponsor's lab has had a long standing interest in IP-10 which along with Mig and I-TAC are IFN inducible CXC chemokines that bind and activate CXCR3 on activated T and NK cells. We have recently found that although all three ligands induce chemotaxis, calcium flux and integrin activation, only I-TAC effectively induces CXCR3 internalization. Moreover, a mAb to CXCR3 blocks only IP-10 binding but not I-TAC or Mig. These data suggest that these ligands make unique contacts with CXCR3 leading to differential receptor activation and effector function. In this application, we will take a molecular genetic approach to generate chimeric receptors to investigate the hypothesis that I-TAC makes a unique contact with an extracellular domain of CXCR3 leading to activation of a specific signal transduction pathway. Additionally, we will use a similar mutagenesis approach to generate chimeric receptors to test the hypothesis that the C-terminus of CXCR3 is necessary and sufficient for signal transduction. Finally, we will use the yeast two hybrid approach to identify proteins that interact with the C- terminus of CXCR3. Due to the importance of selective recruitment of activated T cells during inflammation by these receptor/ligand pairs, identifying agents that specifically block or interrupt CXCR3 function may be therapeutically useful and information about ligand binding sites and ligand induced signal transduction pathways may help develop the most efficacious blocking agents.
| Medoff, Benjamin D; Sauty, Alain; Tager, Andrew M et al. (2002) IFN-gamma-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma. J Immunol 168:5278-86 |
| Dufour, Jennifer H; Dziejman, Michelle; Liu, Michael T et al. (2002) IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J Immunol 168:3195-204 |
| Tager, A M; Dufour, J H; Goodarzi, K et al. (2000) BLTR mediates leukotriene B(4)-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis. J Exp Med 192:439-46 |
