Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3

• Published in: The Journal of experimental medicine Vol. 187; no. 12; pp. 2009 - 2021
• Main Authors: Cole, K E, Strick, C A, Paradis, T J, Ogborne, K T, Loetscher, M, Gladue, R P, Lin, W, Boyd, J G, Moser, B, Wood, D E, Sahagan, B G, Neote, K
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 15.06.1998
• Subjects: Amino Acid Sequence; Astrocytes; Base Sequence; Calcium - metabolism; Chemokine CXCL11; Chemokines, CXC - genetics; Chemokines, CXC - metabolism; Chemotaxis, Leukocyte; Chromosomes, Human, Pair 4; Cloning, Molecular; Desensitization, Immunologic; DNA, Complementary - genetics; Humans; Interferon-gamma - pharmacology; Lymphocyte Activation; Molecular Sequence Data; Protein Binding; Receptors, Chemokine - metabolism; Receptors, CXCR3; RNA, Messenger - biosynthesis; Sequence Analysis, DNA; Sequence Homology, Amino Acid; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.187.12.2009

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-TAC (interferon-inducible T cell alpha chemoattractant), is regulated by interferon (IFN) and has potent chemoattractant activity for interleukin (IL)-2-activated T cells, but not for freshly isolated unstimulated T cells, neutrophils, or monocytes. I-TAC interacts selectively with CXCR3, which is the receptor for two other IFN-inducible chemokines, the IFN-gamma-inducible 10-kD protein (IP-10) and IFN-gamma- induced human monokine (HuMig), but with a significantly higher affinity. In addition, higher potency and efficacy of I-TAC over IP-10 and HuMig is demonstrated by transient mobilization of intracellular calcium as well as chemotactic migration in both activated T cells and transfected cell lines expressing CXCR3. Stimulation of astrocytes with IFN-gamma and IL-1 together results in an approximately 400,000-fold increase in I-TAC mRNA expression, whereas stimulating monocytes with either of the cytokines alone or in combination results in only a 100-fold increase in the level of I-TAC transcript. Moderate expression is also observed in pancreas, lung, thymus, and spleen. The high level of expression in IFN- and IL-1-stimulated astrocytes suggests that I-TAC could be a major chemoattractant for effector T cells involved in the pathophysiology of neuroinflammatory disorders, although I-TAC may also play a role in the migration of activated T cells during IFN-dominated immune responses.