Upregulation of Integrin 6/β1 and Chemokine Receptor CCR1 by Interleukin-12 Promotes the Migration of Human Type 1 Helper T Cells

CD4(+) T helper 1 (Th1) cells and Th2 cells are distinguished based on the pattern of cytokines they are able to produce. Selectin ligands and chemokine receptors are differentially expressed in Th1 and Th2 cells, providing a basis for tissue-specific recruitment of helper T-cell subsets. However, the modes and mechanisms regulating tissue-specific localization of Th1 and Th2 cells are still largely unknown. Here, we show the preferential expression on Th1 cells of the integrin alpha6/beta1, which is distinctly regulated by the Th1-inducing cytokines interleukin-12 (IL-12) and interferon-alfa (IFN-alpha). The pattern of integrin alpha6/beta1 regulation closely mirrors that of the chemokine receptor CCR1. Analysis of signal transducer and activator of transcription 4 (Stat4) activation by IL-12 and IFN-alpha shows distinct signaling kinetics by these cytokines, correlating with the pattern of CCR1 and integrin alpha6/beta1 expression. Unlike IFN-alpha, the ability of IL-12 to generate prolonged intracellular signals appears to be critical for inducing integrin alpha6/beta1 upregulation in Th1 cells. The expression and upregulation of CCR1 and alpha6/beta1 integrin promotes the migration of Th1 cells. These findings suggest that the exquisite regulation of integrin alpha6/beta1 and CCR1 may play an important role in tissue-specific localization of Th1 cells.