The RNA-Binding Protein KSRP Modulates Cytokine Expression of CD4+ T Cells

الملخص EN

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-/-) interferes with T cell activation and polarization.

Polyclonally stimulated KSRP-/- CD4+ 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-/- CD4+ 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-/- CD8+ T cells showed no altered proliferative capacity upon polyclonal stimulation, but supernatants contained lower levels of interferon-γ.

Similar changes in the cytokine expression patterns were also detected in T cells derived from KSRP-/- 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′ untranslated region of IL-13, IL-10, and IFN-γ mRNA in in vitro experiments.

Moreover, since IL-4 mRNA decay was reduced in KSRP-/- CD4+ 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-/- CD4+ 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-/- mice favor Th2-driven immune responses.