IFN-γ-inducible T cell α chemoattractant is a potent stimulator of normal human blood T lymphocyte transendothelial migration: Differential regulation by IFN-γ and TNF-α

Previous studies have shown that the CXC chemokine, IFN-γ-inducible T cell α chemoattractant (I-TAC), was chemotactic for IL-2-activated human T lymphocytes, which express abundant CXCR3. However, because most memory T lymphocytes are also CXCR3⁺, the ability of I-TAC to promote the migration of normal human blood T cells across HUVEC monolayers in Transwell chambers was examined. I-TAC induced a marked (4- to 6-fold) increase in transendothelial migration (TEM) of T cells across unstimulated HUVEC from 5.6 to 28% of input T cells and was substantially more active than IFN-γ-inducible protein-10, another CXCR3 ligand. I-TAC significantly enhanced TEM of T cells across TNF-α, but not across IFN-γ or IFN-γ plus TNF-α-activated HUVEC. IFN-γ or IFN-γ plus TNF-α-activated HUVEC produced substantial amounts of I-TAC, in contrast to TNF-α-treated EC. Both CD4⁺ and CD8⁺ T cells migrated in response to I-TAC to a similar extent, while memory T cells migrated several fold better than naive T cells. Blockade of LFA-1 strongly inhibited I-TAC-induced T cell TEM across unstimulated HUVEC, and ∼50-60% of the TEM across cytokine-activated HUVEC. However, blocking both LFA-1 and very late Ag-4 abolished I-TAC induced T cell TEM. In vivo significant levels of I-TAC were detected in arthritic synovial fluid. Thus, I-TAC is one of the most potent chemoattractants of normal human blood CD4 and CD8 T cell TEM and is likely a major mediator of blood memory T lymphocyte migration to inflammation.