The chemokine receptor CXCR3 is predominantly expressed on activated T lymphocytes. Its agonists, IFN-gamma – inducible chemokines; CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC are involved in Th1-type inflammatory responses such as multiple sclerosis, rheumatoid arthritis, psoriasis, and sarcoidosis. There is a growing body of evidence supporting the existence of splice variants and/or modified CXCR3 receptors such as CXCR3-b and CXCR3-alt which is a limitation in designing antagonists which block CXCR3 function. Interaction of CXCR3 with its ligands induces cellular responses in leukocytes such as chemotactic migration and activation of multiple signaling pathways, including the PI3K pathway, which is thought to be important in directional movement towards a chemokine gradient. In addition, CXCR3 is internalised in response to interaction with its ligands, of which, CXCL11 has been shown to be the most potent inducer of internalisation. In contrast to CXCR3, CXCR3-b has been described as PTX insensitive and unable to induce calcium flux. CXCL4/PF4 has been found to be an additional ligand with unique selectivity toward CXCR3-b. We have detected CXCR3-b expression on primary human T cells at both mRNA and protein level but were unable to induce any chemotaxis towards CXCL4 in human T cells. However stimulation of T cells with CXCL4 resulted in phosphorylation of PKB/Akt as well as Erk1/2 pathways suggesting that CXCR3-b is coupled to downstream biochemical machinery. Surprisingly the biochemical signals were sensitive to PTX treatment, suggesting that coupling is dependant on G alpha i/o proteins. We are currently investigating ability of CXCL4 to cause receptor internalisation and whether distinguished signaling “fingerprints” are associated with CXCR3 and its variants.