Inhibition by IL-12 and IFN-alpha of I-309 and macrophage-derived chemokine production upon TCR triggering of human Th1 cells

Th1 and Th2 cells, which produce distinct sets of cytokines, differentially express several chemokine receptors that may regulate their tissue-specifi c localization. Although the expression pattern and regulation of chemokine s are likely to play a critical role in many immunopathological processes, they remain largely unknown. Here, we investigated the requirements for Th1 and Th2 cells to produce the Th2 cell-attracting chemokines thymus and act ivation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and I-309. TCR triggering of Th1 and Th2 cells leads to production of MDC and I -309 (CCR4 and CCR8 ligands, respectively), whereas TARC (CCR4 ligand) is s electively produced by Th2 cells. Secretion of these chemokines appears to be independent of endogenous production of IL-4 and IFN-gamma. IL-12 and IF N-alpha, cytokines that promote the differentiation of human Th1 cells, sel ectively inhibit secretion and mRNA expression of MDC and I-309 by Th1 cell s. Suppression of I-309 secretion results in a decreased chemotactic effect on Th2 cells transfected with human CCR8, indicating that IL-12 and IFN-al pha may inhibit the recruitment of CCR8-expressing cells such as Th2 cells. The inhibition of Th2 cell-attracting chemokines MDC and I-309 illustrates a novel mechanism by which IL-12 and IFN-alpha could promote and maintain an ongoing Th1 response.