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 so me of them, T-cell costimulation. To date, the only direct property of lymp hotactin (Lptn), the unique member of the C class of chemokines, consists o f T-cell chemoattraction. This report describes a novel function for Lptn i n human T-lymphocyte biology, by demonstrating the direct ability of Lptn t o both inhibit and costimulate CD4(+) and CD8(+) T-cell activation, respect ively. Lptn but not RANTES inhibited CD4(+) T-cell proliferation, through a decreased production of Th1 (interleukin [IL]-2, interferon [IFN]-gamma) b ut 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, a s 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 compensat ed 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, w ortmannin, and genistein, suggesting the involvement of multiple partners i n Lptn signaling. In contrast to CD4(+) cells, Lptn exerted a potent costim ulatory activity on CD8(+) T-cell proliferation and IL-2 secretion. These d ata provide important Insights Into the role of Lptn in differential regula tion of normal human T-cell activation and its possible implication in immu ne response disorders. (C) 2000 by The American Society of Hematology.