DUSP4 deficiency enhances CD25 expression and CD4⁺ T‐cell proliferation without impeding T‐cell development

Abstract

Summary The differentiation and activation of T cells are critically modulated by MAP kinases, which are in turn feed-back regulated by dual-specificity phosphatases (DUSPs) to determine the duration and magnitude of MAP kinase activation. DUSP4 (also known as MKP2) is a MAP kinase-induced DUSP member that is dynamically expressed during thymocyte differentiation. We generated DUSP4-deficient mice to study the function of DUSP4 in T-cell development and activation. Our results showed that thymocyte differentiation and activation-induced MAP kinase phosphorylation were comparable between DUSP4-deficient and wild type mice. Interestingly, activated DUSP4−/− CD4 T cells were hyperproliferative while DUSP4−/− CD8 T cells proliferated normally. Further mechanistic studies suggested that the hyperproliferation of DUSP4−/− CD4 T cells resulted from enhanced CD25 expression and IL-2 signaling through increased STAT5 phosphorylation. Immunization of the DUSP4−/− mice recapitulated the T-cell hyperproliferation phenotype in antigen recall responses, while the profile of Th1/Th2-polarized antibody production was not altered. Combined, these results suggest that other DUSPs may compensate for DUSP4 deficiency in T-cell development, MAP kinase regulation, and Th1/Th2-mediated antibody responses. More importantly, our data indicate that DUSP4 suppress CD4 T-cell proliferation through novel regulations in STAT5 phosphorylation and IL-2 signaling.

Dual-Specificity Phosphatase 14 (DUSP14/MKP6) Negatively Regulates TCR Signaling by Inhibiting TAB1 Activation

“…DUSP10 (also named MKP5) is a positive regulator in T cell proliferation and T cell-mediated immune responses (22). DUSP4 (also named MKP2) suppresses CD4 + T cell proliferation but induces normal Th1/Th2 responses following KLH immunization (23), whereas DUSP4 enhances Th1 responses following Leishmania mexicana infection (21). To our knowledge, our study demonstrates for the first time a novel immune function for DUSP14 in T cells in vivo.…”

“…Only two DUSPs (DUSP4 and DUSP10) are reported to be involved in T cell activation and T cell-mediated immune responses using KO mice (21)(22)(23). DUSP10 (also named MKP5) is a positive regulator in T cell proliferation and T cell-mediated immune responses (22).…”

DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia

“…29 Similar to DUSP6, 53 DUSP4 dephosphorylates ERK and c-Jun N-terminal kinases, 54,55 but also signal transducer and activator of transcription 5, and thereby regulates IL-2 signaling. 56 In vitro, we have shown that DUSP4, but not DUSP6, transcription is upregulated after successive TCR engagement in healthy CD4…”

H3K27 Methylation Dynamics during CD4 T Cell Activation: Regulation of JAK/STAT and IL12RB2 Expression by JMJD3

“…In Figure 4C, we show a heat map based on hierarchical clustering of 30 selected immune activation genes in which H3K27me3 enrichment changed in either direction after activation as a function of time (resting, 1, 5 and 14 days). One gene that dramatically loses the H3K27me3 mark during activation and differentiation is DUSP4, which plays a key role in T cell proliferation (43). This gene is heavily enriched for H3K27me3 at rest in naïve and memory cells, progressing to low H3K27me3 enrichment after activation (Figure 4C–D) for both cell types with concurrent and dramatic upregulation of RNA expression by 1 day in naïve cells (Figure 4E).…”