Deletion of Mucosa‐Associated Lymphoid Tissue Lymphoma Translocation Protein 1 in Mouse T Cells Protects Against Development of Autoimmune Arthritis but Leads to Spontaneous Osteoporosis

Abstract

Objective. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) plays a crucial role in innate and adaptive immune signaling by modulating the threshold for activation of immune cells, including Treg cells. Therefore, MALT-1 is regarded to be an interesting therapeutic target in several immune-mediated diseases. The goal of this study was to examine the role of MALT-1 in experimental animal models of rheumatoid arthritis (RA).Methods. MALT-1 activation was assessed by measuring cleavage of the deubiquitinase CYLD in lymphocytes from mice with collagen-induced arthritis (CIA). Furthermore, the impact of MALT-1 deficiency on arthritis was evaluated in Malt1 KO mice with CIA or with collagen antibody-induced arthritis (CAIA). T cell-specific MALT-1 deficiency was measured in mice with deletion of T cell-specific MALT-1 (Malt1 TcellKO ), and the timedependent effects of MALT-1 deficiency were assessed in mice with deletion of tamoxifen-inducible T cellspecific MALT-1 (Malt1 iTcellKO ). Bone density was determined in MALT-1-deficient mice using micro-computed tomography and femur-bending tests. Reconstitution of Treg cells was performed using adoptive transfer experiments.Results. MALT-1 activation was observed in the lymphocytes of mice with CIA. T cell-specific MALT-1 deletion in the induction phase of arthritis (incidence of arthritis, 25% in control mice versus 0% in Malt1 iTcellKO mice; P < 0.05), but not in the effector phase of arthritis, completely protected mice against the development of CIA. Consistent with this finding, MALT-1 deficiency had no impact on CAIA, an effector phase model of RA. Finally, mice with MALT-1 deficiency showed a spontaneous decrease in bone density (mean ± SEM trabecular thickness, 46.3 ± 0.7 μm in control mice versus 40 ± 1.1 μm in Malt1 KO mice; P < 0.001), which was linked to the loss of Treg cells in these mice.Conclusion. Overall, these data in murine models of RA highlight MALT-1 as a master regulator of T cell activation, which is relevant to the pathogenesis of autoimmune arthritis. Furthermore, these findings show that MALT-1 deficiency can lead to spontaneous osteoporosis, which is associated with impaired Treg cell numbers.

MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner

“…In order to generate conditional Malt1 -KO mice, mice were generated from the EUCOMM Malt1 tm1a(EUCOMM)Hmgu/+ ES cells (85), which were back-crossed to a germ line Flp deleter (86) to generate Malt1 FL /+ mice. These mice were further crossed to the CD4-Cre (87) line and back-crossed to generate Flp-negative T cell-specific Malt1 -KO ( Malt1 FL / FL CD4-Cre ) (88–91). The Malt1 tm1a ( EUCOMM ) Hmgu /+ mice were also back-crossed with a germline Cre-line and back crossed to generate Cre-negative co-isogenic Malt1 − LacZ /− LacZ full-body KO mice.…”

Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood

“…Targeting the proteolytic activity of MALT1 (mucosa-associated lymphoid tissue lymphoma translocated gene 1, paracaspase-1, HsPCA-Ia) has emerged as an attractive strategy for the treatment of lymphomas with oncogenic activation of the MALT1-dependent signaling pathway as well as autoimmune diseases. − However, there are also potential concerns associated with this strategy. On the one hand, protease-inactivated MALT1 knock-in mice display reduced regulatory T cell (Treg) numbers, which is thought to drive inflammation in multiple organs and autoimmunity seen in these animals. − The effect of MALT1 protease inhibition on reducing Treg numbers has, on the other hand, recently been suggested to potentiate efficacy of check-point immunotherapy in cancer. , Overall, the therapeutic potential of MALT1 protease inhibitors remains an open question and there is a need for suitable compounds to explore the in vivo efficacy and safety profile of MALT1 protease inhibition. Several classes of covalent − and noncovalent allosteric − MALT1 protease inhibitors have been used to probe the effects of pharmacological MALT1 inhibition.…”

Requirement of Mucosa‐Associated Lymphoid Tissue Lymphoma Translocation Protein 1 Protease Activity for Fcγ Receptor–Induced Arthritis, but Not Fcγ Receptor–Mediated Platelet Elimination, in Mice

“…In the T cell–dependent collagen‐induced arthritis model, MALT‐1 deletion in T cells affected only disease onset and not the course of the disease . This finding suggests that the role of MALT‐1 in early arthritis, during the formation of autoantibodies, is most prominent in the adaptive immune system, while MALT‐1 and the CBM complex are most important in the myeloid compartment in established disease, once the autoantibodies are formed . Given the multiple biologic pathways and cell types that contribute to arthritis, MALT‐1 protease represents an attractive therapeutic target.…”