Malt1 Protease Deficiency in Mice Disrupts Immune Homeostasis at Environmental Barriers and Drives Systemic T Cell-Mediated Autoimmunity.
Kea MartinRatiba TouilYeter KolbGrozdan CvijeticKiichi MurakamiLaura IsraelFernanda DuraesDavid BuffetAnton GlückSatoru NiwaMarc BigaudTobias JuntNatasa ZamurovicPhilip SmithKathy D McCoyPamela S OhashiFrédéric BornancinThomas CalzasciaPublished in: Journal of immunology (Baltimore, Md. : 1950) (2019)
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 MALT1 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 MALT1.
Keyphrases
- regulatory t cells
- dendritic cells
- multiple sclerosis
- induced apoptosis
- cell cycle arrest
- signaling pathway
- type diabetes
- transcription factor
- microbial community
- immune response
- ulcerative colitis
- cell death
- risk assessment
- deep learning
- machine learning
- skeletal muscle
- climate change
- artificial intelligence
- lps induced