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Updated: Jun 30, 2025
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
T cell activation contributes to purifying selection against the MELAS-associated m.3243A>G pathogenic variant in
Melissa A Walker1,2,3, Shuqiang Li3,4,5, Kenneth J Livak4,5
1Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Abstract:
T cells have been shown to maintain a lower percentage (heteroplasmy) of the pathogenic m.3243A>G variant (MT-TL1, associated with maternally inherited diabetes and deafness [MIDD] and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]). The mechanism(s) underlying this purifying selection, however, remain unknown. Here we report that purified patient memory CD4+ T cells have lower bulk m.3243A>G heteroplasmy compared to naïve CD4+ T cells. In vitro activation of naïve CD4+ m.3243A>G patient T cells results in lower bulk m.3243A>G heteroplasmy after proliferation. Finally, m.3243A>G patient T cell receptor repertoire sequencing reveals relative oligoclonality compared to controls. These data support a role for T cell activation in peripheral, purifying selection against high m.3243A>G heteroplasmy T cells at the level of the cell, in a likely cell-autonomous fashion.
Insights
T cells with the m.3243A>G mitochondrial variant show reduced levels after activation. This suggests T cell activation drives purifying selection against cells with high variant heteroplasmy.
Area of Science:
- Mitochondrial genetics
- Immunology
- Cell biology
Background:
- The m.3243A>G variant in MT-TL1 is linked to maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).
- T cells exhibit lower heteroplasmy of this pathogenic variant, but the underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the mechanisms of purifying selection against the m.3243A>G variant in T cells.
- To determine if T cell activation influences variant heteroplasmy.
Main Methods:
- Comparison of m.3243A>G heteroplasmy in purified memory and naïve CD4+ T cells from patients.
- In vitro activation and proliferation assays of patient T cells.
- T cell receptor repertoire sequencing.
Main Results:
- Memory CD4+ T cells showed lower m.3243A>G heteroplasmy than naïve CD4+ T cells.
- In vitro T cell activation led to decreased heteroplasmy after proliferation.
- T cell receptor sequencing indicated oligoclonality in patient T cells compared to controls.
Conclusions:
- T cell activation plays a role in peripheral, cell-autonomous purifying selection against T cells with high m.3243A>G heteroplasmy.
- These findings provide insights into the regulation of mitochondrial DNA variants within the immune system.
