The C-class chemokine, lymphotactin, impairs the induction of Th1-type lymphokines in human CD4(+) T cells.
Chemokines are involved in the regulation of leukocyte migration and for some of them, T-cell costimulation. To date, the only direct property of lymphotactin (Lptn), the unique member of the C class of chemokines, consists of T-cell chemoattraction. This report describes a novel function for Lptn in human T-lymphocyte biology, by demonstrating the direct ability of Lptn to both inhibit and costimulate CD4(+) and CD8(+) T-cell activation, respectively. Lptn but not RANTES inhibited CD4(+) T-cell proliferation, through a decreased production of Th1 (interleukin [IL]-2, interferon [IFN]-gamma) but not Th2 (IL-4, IL-13) lymphokines, and decreased IL-2R alpha expression. Transfections in Jurkat cells showed a Lptn-mediated transcriptional down-regulation of gene-promoter activities specific for Th1-type lymphokines, as well as of nuclear factor of activated T cells (NF-AT) but not AP-1 or NF-KB enhancer activities. This suppressive action of Lptn could be compensated by overexpression of NF-ATc but not NF-ATp. CD4(+) T-cell proliferation was completely restored by exogenous IL-2 or reversed by pertussis toxin, wortmannin, and genistein, suggesting the involvement of multiple partners in Lptn signaling. In contrast to CD4(+) cells, Lptn exerted a potent costimulatory activity on CD8(+) T-cell proliferation and IL-2 secretion. These data provide important insights into the role of Lptn in differential regulation of normal human T-cell activation and its possible implication in immune response disorders. (Blood. 2000;96:420-428)
Cerdan
C
C
National Institute of Health and Medical Research, University of Méditerranée, Marseille, France. cerdan@marseille.inserm.fr
Serfling
E
E
Olive
D
D
D000730:Androstadienes / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D019744:Chemokines, C; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018793:Interleukin-13 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008222:Lymphokines / Q000235:genetics / Q000494:pharmacology*; D037342:Pertussis Toxin; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D019744:Chemokines, C; D004791:Enzyme Inhibitors; D018793:Interleukin-13; D007376:Interleukin-2; D008222:Lymphokines; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D010566:Virulence Factors, Bordetella; C092390:XCL1 protein, human; C018997:lymphotactin; D015847:Interleukin-4; D007371:Interferon-gamma; D019833:Genistein; D037342:Pertussis Toxin; D000077191:Wortmannin