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Evaluation of T Follicular Helper Cells and Germinal Center Response During Influenza A Virus Infection in Mice
Published on: June 27, 2020
The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation
Wangpeng Gu1,2, Jia Zhang2, Qing Li2
1Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
Abstract:
The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FINmajor (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.
Insights
Mulibrey nanism, caused by TRIM37 gene variants, leads to recurrent infections. The TRIM37 protein is crucial for follicular helper T (TFH) cell development and antibody production, explaining immune deficiencies in patients.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Mulibrey (Muscle-liver-brain-eye) nanism is an autosomal recessive disorder linked to TRIM37 gene variants.
- Patients exhibit severe growth failure, constrictive pericarditis, and a high incidence of severe respiratory infections.
- Recurrent infections contribute to increased mortality rates in Mulibrey nanism patients.
Purpose of the Study:
- To investigate the association between TRIM37 variants and recurrent infections.
- To elucidate the immunological mechanisms underlying impaired T cell function and antibody production in Mulibrey nanism.
- To understand the role of TRIM37 in follicular helper T (TFH) cell differentiation and function.
Main Methods:
- Utilized Trim37 FINmajor variants and Trim37 knockout mouse models to study susceptibility to influenza virus infection.
- Analyzed defects in follicular helper T (TFH) cell development and antibody production in affected models.
- Investigated the molecular mechanism of TRIM37's action on Bcl6, including its E3 ligase activity and protein interactions.
Main Results:
- TRIM37 variants are associated with increased susceptibility to recurrent infections, including influenza virus.
- Trim37 deficiency impairs follicular helper T (TFH) cell development and reduces antibody production.
- TRIM37 regulates TFH cell differentiation by catalyzing polyubiquitination of Bcl6, protecting it from degradation via its E3 ligase and MATH domains.
Conclusions:
- The TRIM37-Bcl6 axis is critical for proper TFH cell development and high-affinity antibody production.
- Dysregulation of the TRIM37-Bcl6 pathway contributes to the immunodeficiency observed in Mulibrey nanism.
- Understanding this mechanism provides insight into recurrent respiratory infections in Mulibrey nanism patients.
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