Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection

Area of Science:

• Immunology
• Cell Biology
• Proteasome Biology

Background:

• Cortical thymic epithelial cells (cTECs) present antigens crucial for T cell development.
• The thymoproteasome subunit-β5T is unique to cTECs and essential for CD8 T cell development.
• The immunoproteasome subunit-β5i is found in other thymic antigen-presenting cells (APCs).

Purpose of the Study:

• To investigate the specific role of β5T in positive selection of T cells.
• To determine if β5i can functionally replace β5T in cTECs.
• To understand how the thymoproteasome influences T cell repertoire selection.

Main Methods:

• Generation of β5t(5i) knockin mice to alter peptide repertoire in cTECs.
• Crossing β5t(5i) mice with β5i(-/-) mice for exclusive cTEC β5i expression.
• Utilizing an Nur77(GFP) reporter to assess T cell reactivity.

Main Results:

• Mice with β5i replacing β5T in cTECs did not support normal positive selection, indicating β5T's unique function.
• β5i cannot functionally replace β5T, suggesting β5T generates intrinsically superior peptides for positive selection.
• T cells generated without β5T showed increased self-reactivity and a CD44(hi) memory phenotype.

Conclusions:

• The thymoproteasome, via β5T, generates peptides optimized for selecting weakly self-reactive naive T cell clones.
• This process ensures a diverse and functional T cell repertoire for the immune system.
• β5T's unique function is critical for proper T cell maturation and self-tolerance.