MALT1 is an intrinsic regulator of regulatory T cells.

Regulatory T cells (Tregs) are crucial for the maintenance of immunological self-tolerance and their absence or dysfunction can lead to autoimmunity. However, the molecular pathways that govern Treg biology remain obscure. In this study, we show that the nuclear factor-κB signalling mediator mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important novel regulator of both Tregs originating in the thymus ('natural' or nTregs) and Tregs induced to differentiate from naive thymocyte helper (Th) cells in the periphery ('induced' or iTregs). Our examination of mice deficient for MALT1 revealed that these mutants have a reduced number of total Tregs. In young Malt1-/- mice, nTregs are totally absent and iTreg are diminished in the periphery. Interestingly, total Treg numbers increase in older Malt1-/- mice as well as in Malt1-/- mice subjected to experimentally induced inflammation. iTregs isolated from WT and Malt1-/- mice were indistinguishable with respect to their ability to suppress the activities of effector T cells, but Malt1-/- iTregs expressed higher levels of Toll-like receptor (TLR) 2. Treatment of WT and Malt1-/- Th cells in vitro with the TLR2 ligand Pam3Cys strongly enhanced the induction and proliferation of Malt1-/- iTregs. Our data suggest that MALT1 supports nTreg development in the thymus but suppresses iTreg induction in the periphery during inflammation. Our data position MALT1 as a key molecule that contributes to immune tolerance at steady-state while facilitating immune reactivity under stress conditions.

Chronophin is a glial tumor modifier involved in the regulation of glioblastoma growth and invasiveness.

Glioblastoma is the most aggressive primary brain tumor in adults. Although the rapid recurrence of glioblastomas after treatment is a major clinical challenge, the relationships between tumor growth and intracerebral spread remain poorly understood. We have identified the cofilin phosphatase chronophin (gene name: pyridoxal phosphatase, PDXP) as a glial tumor modifier. Monoallelic PDXP loss was frequent in four independent human astrocytic tumor cohorts and increased with tumor grade. We found that aberrant PDXP promoter methylation can be a mechanism leading to further chronophin downregulation in glioblastomas, which correlated with shorter glioblastoma patient survival. Moreover, we observed an inverse association between chronophin protein expression and cofilin phosphorylation levels in glioma tissue samples. Chronophin-deficient glioblastoma cells showed elevated cofilin phosphorylation, an increase in polymerized actin, a higher directionality of cell migration, and elevated in vitro invasiveness. Tumor growth of chronophin-depleted glioblastoma cells xenografted into the immunodeficient mouse brain was strongly impaired. Our study suggests a mechanism whereby the genetic and epigenetic alterations of PDXP resulting in altered chronophin expression may regulate the interplay between glioma cell proliferation and invasion.