MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner

Abstract

MALT1 is a central signaling component in innate and adaptive immunity by regulating NF-κB and other key signaling pathways in different cell types. Activities of MALT1 are mediated by its scaffold and protease functions. Because of its role in lymphocyte activation and proliferation, inhibition of MALT1 proteolytic activity is of high interest for therapeutic targeting in autoimmunity and certain lymphomas. However, recent studies showing that Malt1 protease-dead knock-in ( Malt1 -PD) mice suffer from autoimmune disease have somewhat tempered the initial enthusiasm. Although it has been proposed that an imbalance between immune suppressive regulatory T cells (Tregs) and activated effector CD4 + T cells plays a key role in the autoimmune phenotype of Malt1 -PD mice, the specific contribution of MALT1 proteolytic activity in T cells remains unclear. Using T cell-conditional Malt1 protease-dead knock-in ( Malt1 -PDT) mice, we here demonstrate that MALT1 has a T cell-intrinsic role in regulating the homeostasis and function of thymic and peripheral T cells. T cell-specific ablation of MALT1 proteolytic activity phenocopies mice in which MALT1 proteolytic activity has been genetically inactivated in all cell types. The Malt1 -PDT mice have a reduced number of Tregs in the thymus and periphery, although the effect in the periphery is less pronounced compared to full-body Malt1 -PD mice, indicating that also other cell types may promote Treg induction in a MALT1 protease-dependent manner. Despite the difference in peripheral Treg number, both T cell-specific and full-body Malt1 -PD mice develop ataxia and multi-organ inflammation to a similar extent. Furthermore, reconstitution of the full-body Malt1 -PD mice with T cell-specific expression of wild-type human MALT1 eliminated all signs of autoimmunity. Together, these findings establish an important T cell-intrinsic role of MALT1 proteolytic activity in the suppression of autoimmune responses.

Malt1 Protease Deficiency in Mice Disrupts Immune Homeostasis at Environmental Barriers and Drives Systemic T Cell–Mediated Autoimmunity

“…Although the reduced frequency of Tregs in Malt1PD mice may on its own be sufficient to drive the inflammatory disease, the absence of Malt1 protease function in Tregs may also impact additional Treg immunoregulatory mechanisms critical for the maintenance of immune homeostasis in vivo. To this point, four recent studies provided critical novel insights into the functional consequences of the disruption of the CBM complex in Foxp3 + Tregs via the genetic deletion of CARD11, BCL10, or MALT1 or via the genetic inactivation of the MALT1 protease (85)(86)(87)(88). In line with our findings, Cheng et al reported that Malt1PD Tregs display an overall normal in vitro suppression activity, whereas Rosenbaum et al suggested a partial reduction in in vitro suppressive activity.…”

“…Consistent with this, both groups observed that the genetic inactivation of the Malt1 protease function selectively in Foxp3 + Tregs is sufficient to drive a severe IPEX-like inflammatory disease. In line with this, Demeyer et al (86) reported that mice characterized by a T cell-restricted Malt1 protease deficiency develop an IPEX-like syndrome similar to the one reported in mice with a systemic Malt1 protease defect. Additional data involving the use of Malt1PD Tregs or WT Tregs treated with a MALT1 inhibitor suggest that inhibition of the Malt1 protease function results in defective expression of CTLA4, IL-10, and TGF-b (85,88).…”

Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology

“…In line with this, T cell-restricted inactivation of MALT1 protease is sufficient to cause an IPEXlike pathology similar to the one observed in full-body MALT1 PD animals (27). Of note, using MALT1 PD Treg cells or WT Treg cells treated with a MALT1 inhibitor, various groups suggested that impairment of MALT1 protease function in Tregs leads to defective upregulation of several molecules associated with Treg suppressive activity, such as CTLA-4, IL-10, and TGF-β (26,27,29). Overall, these studies indicate that CBM components including MALT1 protease function are critical to maintain the optimal suppressive function and identity of Tregs in vivo.…”

“…Genetic deletion of CARD11, BCL10, or MALT1, as well as the genetic inactivation of the MALT1 protease selectively in Foxp3 + Tregs was associated with Treg dysfunction in vivo and development of an IPEXlike disease (26,28,29). In line with this, T cell-restricted inactivation of MALT1 protease is sufficient to cause an IPEXlike pathology similar to the one observed in full-body MALT1 PD animals (27). Of note, using MALT1 PD Treg cells or WT Treg cells treated with a MALT1 inhibitor, various groups suggested that impairment of MALT1 protease function in Tregs leads to defective upregulation of several molecules associated with Treg suppressive activity, such as CTLA-4, IL-10, and TGF-β (26,27,29).…”

“…By contrast, the lack of lymphocyte effector functions in immunodeficient MALT1 KO mice results in only mild clinical symptoms despite a more severe reduction in Treg cells (13)(14)(15)(16). Very recently, four novel reports elucidated the role of the CBM complex in Treg function and the maintenance of immune homeostasis (26)(27)(28)(29). Genetic deletion of CARD11, BCL10, or MALT1, as well as the genetic inactivation of the MALT1 protease selectively in Foxp3 + Tregs was associated with Treg dysfunction in vivo and development of an IPEXlike disease (26,28,29).…”