Malt1 Protease Is Critical in Maintaining Function of Regulatory T Cells and May Be a Therapeutic Target for Antitumor Immunity

Abstract

The paracaspase Malt1 is a key molecule in mediating Ag receptor-induced NF-κB activation in lymphocytes, but the role of Malt1 in the function of regulatory T (Treg) cells is still unclear. In this article, we reported that specific deletion of Malt1 in Treg cells would lead to <i>Scurfy</i>-like lethal autoimmune disease, which was caused by Treg cell dysfunction but not number loss. Interestingly, <i>Foxp3^CreMalt1^fl/C472A</i> mice, in which Malt1 protease was specifically inactivated in Treg cells, also displayed spontaneous inflammatory disorders, with severe hair loss and skin hyperplasia. Consistently, <i>Foxp3^CreMalt1^fl/C472A</i> mice showed enhanced antitumor response because of their decreased function and infiltration of Treg cells, as well as reduced CD8⁺ T cell exhaustion. Gene expression profiling analysis revealed dysregulated expression pattern of Treg effector genes upon Malt1 deletion or its protease inactivation. Together, our data unraveled a critical role of Malt1, especially its protease activity, in maintaining homeostasis and function of Treg cells.