A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The thymoproteasome's β5t subunit, encoded by Psmb11, is crucial for CD8+ T cell selection in mouse thymus.
• This subunit is specifically expressed in cortical thymic epithelial cells (cTECs).

Purpose of the Study:

• To investigate the functional impact of a common human PSMB11 variation on thymoproteasome activity and T cell development.
• To assess the in vivo consequences of this variation in a mouse model.

Main Methods:

• Introduction of the human PSMB11 variation into the mouse genome.
• Analysis of β5t expression in cTECs.
• Quantification of CD8+ T cell populations.
• Clinical observation of human individuals with the variation.

Main Results:

• The human PSMB11 variation alters the β5t amino acid sequence, affecting the processing of active β5t proteins.
• Heterozygous mice exhibited reduced β5t expression in cTECs.
• Homozygous mice showed a significant reduction in CD8+ T cell cellularity.
• No severe health issues were noted in heterozygous or homozygous human carriers.

Conclusions:

• The PSMB11 variation impacts thymoproteasome function and CD8+ T cell selection in mice.
• Further long-term studies in humans are needed to fully understand the role of thymoproteasome-dependent T cell selection.