TGF-β conditions intestinal T cells to express increased levels of miR-155, associated with down-regulation of IL-2 and itk mRNA

Transforming growth factor (TGF)-beta, is an immunosuppressive cytokine that inhibits T-cell activation. We hypothesized that TGF-beta mediates its immunoinhibitory effects by modulation of micro RNA (miRNA)-155 (miR-155). Interleukin (IL)-2 and interferon-gamma are down-regulated by TGF-beta in activated CD4 peripheral blood T cells and lamina propria T cells (LPT), but miR-155 is upregulated ninefold specifically in LPT. Consequently, this study focuses on the role of TGF-beta-enhanced miR-155 on LPT immune responses. TGF-beta induces miR-155 in both freshly isolated and LPT lymphoblasts, whereas other inducible miRNAs are not regulated by TGF-beta. Using MAMI bioinformatics database, we determined that inducible T-cell kinase (itk) is a functional target of miR-155 that exhibits an inverse mRNA response to that of miR-155. To determine experimentally that miR-155 regulates itk, transfection experiments were performed that demonstrated miR-155 overexpression decreased itk and IL-2 mRNA, whereas antagonism of miR-155 restored both mRNAs in activated cells. These findings describe a TGF-beta-dependent function for miR-155 in modulating cytokine and T-cell immune responses in the gut.