Mst1/Mst2 Regulate Development and Function of Regulatory T Cells through Modulation of Foxo1/Foxo3 Stability in Autoimmune Disease

Abstract

Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1−/− mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1−/− bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency–mediated human immunodeficiency syndrome.

SLy1 regulates T‐cell proliferation during Listeria monocytogenes infection in a Foxo1‐dependent manner

“…In the latter Foxo1 becomes dephosphorylated [40] or degraded [41,42]. More detailed analyses excluded a degradation of Foxo1 but demonstrated an accelerated Foxo1 dephosphorylation in SLy1 KO T cells after TCR stimulation, resulting in a faster reimport to the nucleus and induced expression of target genes, such as p27 and p130.…”

Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis

“…The majority of CpG sites showed a moderate increase (between 1.5-and 5-fold) in DNA methylation upon Tet2 deletion and/or RhoA G17V expression, which might be associated with the 20% decrease in FoxO1 gene expression in Tet2 -/-and Tet2 -/-RhoA G17V CD4 + T cells ( Figure 6A). Next, to identify potential upstream factors that might control FoxO1 phosphorylation, we focused on Akt and MST1, two protein kinases that are most prominently known to regulate this process (48). We performed Western blotting to determine the total prolevels in all the groups remained unaltered (Supplemental Figure 4E).…”

PP6 Controls T Cell Development and Homeostasis by Negatively Regulating Distal TCR Signaling

“…Bone marrow chimeras were generated by i.v. transfer of T cell-depleted bone marrow into sublethally irradiated B6.SJL mice as described previously (20). All mice were kept in specific pathogen-free conditions, and animal-related procedures were approved by the Animal Care and Use Committee of the Institute of Developmental Biology and Molecular Medicine at Fudan University.…”