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

• Published in: The Journal of immunology (1950) 2019-12, Vol.203 (11), p.2791-2806
• Main Authors: Martin, Kea, Touil, Ratiba, Kolb, Yeter, Cvijetic, Grozdan, Murakami, Kiichi, Israel, Laura, Duraes, Fernanda, Buffet, David, Glück, Anton, Niwa, Satoru, Bigaud, Marc, Junt, Tobias, Zamurovic, Natasa, Smith, Philip, McCoy, Kathy D, Ohashi, Pamela S, Bornancin, Frédéric, Calzascia, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity; Autoimmunity - immunology; Homeostasis - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - deficiency; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - genetics; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1900327

The paracaspase Malt1 is a key regulator of canonical NF-κB activation downstream of multiple receptors in both immune and nonimmune cells. Genetic disruption of Malt1 protease function in mice and mutations in humans results in reduced regulatory T cells and a progressive multiorgan inflammatory pathology. In this study, we evaluated the altered immune homeostasis and autoimmune disease in Malt1 protease-deficient (Malt1PD) mice and the Ags driving disease manifestations. Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis. Conversely, the disease was driven by a polyclonal T cell population directed against self-antigens. Characterization of the Malt1PD T cell compartment revealed expansion of T effector memory cells and concomitant loss of a CD4 T cell population that phenotypically resembles anergic T cells. Therefore, we propose that the compromised regulatory T cell compartment in Malt1PD animals prevents the efficient maintenance of anergy and supports the progressive expansion of pathogenic, IFN-γ-producing T cells. Overall, our data revealed a crucial role of the Malt1 protease for the maintenance of intestinal and systemic immune homeostasis, which might provide insights into the mechanisms underlying IPEX-related diseases associated with mutations in .