MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner.

Annelies Demeyer,Mathijs Baens,Yasmine Driege,Marja Kreike,Tino Hochepied,Jens Staal,Rudi Beyaert,Ioannis Skordos

doi:10.3389/fimmu.2019.01898

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.

Highlights

MALT1 (PCASP1 or paracaspase-1) is ubiquitously expressed in multiple cell types, where it is involved in signaling leading to pro-inflammatory gene expression
As for the Tregs, here the percentage of CTLA-4 surface-positive CD44+CD4+ T cells was found to be reduced in young disease-free Malt1-PDT mice (Figure 4H). These results clearly demonstrate that MALT1 proteolytic activity in T cells regulates CTLA-4 surface expression in Tregs and CD44+CD4+ T cells, indicating that MALT1 proteolytic activity influences Treg functionality in a T cell-intrinsic manner, since even a moderate decrease in CTLA4 expression can lead to autoimmunity in humans [61]
MALT1 proteolytic activity plays a key role in both immune cells and non-immune cells [62, 63], and mice expressing a catalytically inactive MALT1 mutant (Malt1-PD mice) were previously shown to suffer from severe autoimmunity [4,5,6, 47]

Summary

Introduction

MALT1 (PCASP1 or paracaspase-1) is ubiquitously expressed in multiple cell types, where it is involved in signaling leading to pro-inflammatory gene expression. The best known role of MALT1 is the activation of NF-κB signaling in response to T cell and B cell antigen receptor triggering, which is critical for the adaptive immune system. A MALT1-deficient patient suffering from recurrent infections was cured by transplantation of mostly T cells [8] This indicates a major role for T cells as a determinant of the compromised immunity phenotypes caused by MALT1 deficiency. B cells can be alternatively activated by innate receptors in a MALT1-independent manner This might explain the lower phenotypic impact of MALT1 deficiency in B cells [2, 6, 7, 9]. Apart from its role in immune signaling through loss-of-function, aberrant activation or expression of MALT1 has been associated to different forms of B cell cancer, such as ABC-DLBCL [11,12,13,14], low-grade MALT lymphomas [15,16,17,18,19], and a complex type of PID called B cell expansion with NF-κB and T cell anergy (BENTA) [20, 21]

Methods

Results

Conclusion