IFN-gamma-inducible T cell alpha chemoattractant is a potent stimulator of normal human blood T lymphocyte transendothelial migration: differential regulation by IFN-gamma and TNF-alpha.
Previous studies have shown that the CXC chemokine, IFN-gamma-inducible T cell alpha 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-gamma-inducible protein-10, another CXCR3 ligand. I-TAC significantly enhanced TEM of T cells across TNF-alpha, but not across IFN-gamma or IFN-gamma plus TNF-alpha-activated HUVEC. IFN-gamma or IFN-gamma plus TNF-alpha-activated HUVEC produced substantial amounts of I-TAC, in contrast to TNF-alpha-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 approximately 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.
Mohan
Karkada
K
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
Ding
Ziqiang
Z
Hanly
John
J
Issekutz
Thomas B
TB
D019138:Antibodies, Blocking / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000378:metabolism / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D016207:Cytokines / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology; D007371:Interferon-gamma / Q000097:blood / Q000502:physiology*; D007376:Interleukin-2 / Q000494:pharmacology; D007399:Interphase / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000502:physiology; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors / Q000502:physiology; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014471:Umbilical Veins
D019138:Antibodies, Blocking; C515202:CXCL11 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D016207:Cytokines; D039041:Integrin alpha4beta1; D016023:Integrins; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma