UBC Theses and Dissertations
The role of MALT1 in T cell immunity Kang, Sohyeong
Individuals with combined immunodeficiency exhibit normal frequencies of T and B cells but suffer from severe recurrent infections. A child admitted to BCCH displayed a novel clinical presentation of combined immunodeficiency with immune dysregulation. The patient was found to inherit homozygous missense mutations in the MALT1 gene from her consanguineous parents. MALT1 is important in activating the NF-kB pathway upon TCR stimulation. MALT1 functions by two different mechanisms: (1) as a scaffolding molecule bringing CARD11 and BCL-10 to form the CBM signalosome complex and (2) as a caspase-like protease cleaving substrates to regulate NF-kB signaling. Studies in Malt1¯/¯ mice have revealed weakened T cell immunity whereas mice expressing MALT1 lacking paracaspase activity are prone to fetal autoimmunity. In addition, patients with MALT1 mutations shared similar clinical characteristics, experiencing chronic infections and gastrointestinal inflammation. Together, these findings raise questions regarding the nature of our patient’s mutant MALT1 protein and the role it plays in her pro-inflammatory phenotype. Our data have shown that MALT1 is essential for IL-2 production in CD4 T cells despite the dispensable role in regulatory T cell development. In addition, we demonstrate that MALT1 plays a crucial role in effector function of Th1 and Th17 cells. Analysis of the patient’s MALT1 scaffolding and paracaspase activity revealed that the patient’s MALT1 mutations act as a hypomorphic allele. Unlike our patient, Malt1¯/¯ mice do not exhibit constitutive immune activation and severe intestinal inflammation. A limited pathogen exposure may be responsible for the discrepancy in phenotype of the patient and Malt1¯/¯ mice. Hence, we introduced LCMV pathogen to Malt1¯/¯ mice and assessed the role of MALT1 in anti-viral T cell immune responses. Malt1¯/¯ mice exhibited severely impaired effector function of viral-specific CD4 T cells. However, we found that MALT1 is dispensable for the generation and effector function of viral-specific CD8 T cells. Further, MALT1 alters the expression of T cell differentiation markers, whereas it does not modulate activation and inhibitory receptors upon viral infection. Collectively, our studies demonstrate that MALT1 plays a pivotal role in CD4 T cell immune responses, yet is not required for CD8 T cell anti-viral immunity.
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