Description:
<jats:p>The KH-type splicing regulatory protein (KSRP) is a RNA-binding protein, which regulates the stability of many mRNAs encoding immune-relevant proteins. As KSRP regulates innate immune responses, for instance by the modulation of type I interferon mRNA stability, we were interested whether knockdown of the protein (KSRP<jats:sup>-/-</jats:sup>) interferes with T cell activation and polarization. Polyclonally stimulated KSRP<jats:sup>-/-</jats:sup>CD4<jats:sup>+</jats:sup>T cells proliferated at a higher extent and higher frequency and expressed the activation marker CD25 more than wild-type T cells. In supernatants of stimulated KSRP<jats:sup>-/-</jats:sup>CD4<jats:sup>+</jats:sup>T cells, levels of IL-5, IL-9, IL-10, and IL-13 were observed to be increased compared to those of the control group. KSRP<jats:sup>-/-</jats:sup>CD8<jats:sup>+</jats:sup>T cells showed no altered proliferative capacity upon polyclonal stimulation, but supernatants contained lower levels of interferon-<jats:italic>γ</jats:italic>. Similar changes in the cytokine expression patterns were also detected in T cells derived from KSRP<jats:sup>-/-</jats:sup>mice undergoing arthritis induction indicative of a pathophysiological role of KSRP-dependent T cell polarization. We demonstrated the direct binding of KSRP to the 3<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:msup><mml:mrow /><mml:mrow><mml:mo>′</mml:mo></mml:mrow></mml:msup></mml:math>untranslated region of IL-13, IL-10, and IFN-<jats:italic>γ</jats:italic>mRNA in in vitro experiments. Moreover, since IL-4 mRNA decay was reduced in KSRP<jats:sup>-/-</jats:sup>CD4<jats:sup>+</jats:sup>T cells, we identify KSRP as a negative regulator of IL-4 expression. These data indicate that overexpression of IL-4, which constitutes the primary inducer of Th2 polarization, may cause the Th2 bias of polyclonally stimulated KSRP<jats:sup>-/-</jats:sup>CD4<jats:sup>+</jats:sup>T cells. This is the first report demonstrating that KSRP is involved in the regulation of T cell responses. We present strong evidence that T cells derived from KSRP<jats:sup>-/-</jats:sup>mice favor Th2-driven immune responses.</jats:p>