A novel spontaneous mutation in the TAP2 gene unravels its role in macrophage survival

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• The transporter associated with antigen processing (TAP) is crucial for antigen presentation.
• TAP2 deficiency is linked to immune system impairments, primarily affecting T cells.

Purpose of the Study:

• To characterize a novel mouse strain with a spontaneous mutation in the TAP2 gene.
• To investigate the immunological and cellular consequences of complete TAP2 deficiency.

Main Methods:

• Genetic sequencing to identify the point mutation in the TAP2 gene.
• Flow cytometry to assess immune cell populations (CD8+ T cells).
• Analysis of MHC-I expression on cell surfaces.
• Macrophage enumeration and survival assays in vivo and ex vivo.

Main Results:

• A new mouse strain, 'eightless,' with a C-to-T substitution in exon 5 of TAP2 was identified.
• Eightless mice lack CD8+ T cells and exhibit reduced surface MHC-I expression due to TAP2 deficiency.
• A significant reduction in peritoneal macrophages was observed in eightless mice.
• Eightless macrophages demonstrated impaired survival following peritoneal inflammation.

Conclusions:

• This study presents the first complete TAP2 knockout mouse model.
• The observed macrophage defects in eightless mice offer a potential explanation for the phagocyte-related clinical manifestations in human TAP2 deficiency syndrome.
• The findings highlight a broader role for TAP2 beyond adaptive immunity.