INTERFERON-INDUCIBLE T-CELL ALPHA-CHEMOATTRACTANT (I-TAC) - A NOVEL NON-ELR CXC CHEMOKINE WITH POTENT ACTIVITY ON ACTIVATED T-CELLS THROUGHSELECTIVE HIGH-AFFINITY BINDING TO CXCR3

Chemokines are essential mediators of normal leukocyte trafficking as well as of leukocyte recruitment during inflammation. We describe here a novel non-ELR CXC chemokine identified through sequence analysis of cDNAs derived from cytokine-activated primary human astrocytes. This novel chemokine, referred to as I-TAG (interferon-inducible T cell alp ha chemoattractant), is regulated by interferon (IFN) and has potent c hemoattractant activity for interleukin (IL)-2-activated T cells, but not for freshly isolated unstimulated T cells, neutrophils, or monocyt es. I-TAG interacts selectively with CXCR3, which is the receptor for two other IFN-inducible chemokines, the IFN-gamma-inducible 10-kD prot ein (IP-10) and IFN-gamma-induced human monokine (HuMig), but with a s ignificantly higher affinity. In addition, higher potency and efficacy of I-TAG over IP-10 and HuMig is demonstrated by transient mobilizati on of intracellular calcium as well as chemotactic migration in both a ctivated T cells and transfected cell lines expressing CXCR3. Stimulat ion of astrocytes with IFN-gamma and IL-1 together results in an simil ar to 400,000-fold increase in I-TAG mRNA expression, whereas stimulat ing monocytes with either of the cytokines alone or in combination res ults in only a 100-fold increase in the level of I-TAC transcript. Mod erate expression is also observed in pancreas, lung, thymus, and splee n. The high level of expression in IFN- and IL-1-stimulated astrocytes suggests that I-TAC could be a major chemoattractant for effector T c ells involved in the pathophysiology of neuroinflammatory disorders, a lthough I-TAG may also play a role in the migration of activated T cel ls during IFN-dominated immune responses.