Importance of CD3AP in the assembly of the T-cell receptor and other immune receptor complexes

• Applicant: Professor Dr. Stephan Hailfinger
• Subject Area: Immunology ; Biochemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516330609

T cells are central players in the clearance of pathogens and transformed cells. The recognition of non-self antigens is facilitated by the T-cell receptor (TCR)-CD3 complex consisting of two TCR and six CD3 subunits. TCR-CD3 complex assembly occurs in the endoplasmic reticulum and is tightly controlled. Only the fully assembled complex is transported to the plasma membrane, whereas unpaired TCR and CD3 chains are rapidly degraded. Using an approach involving CD3ε pull-down and subsequent mass spectrometry analyses, we identified a so far uncharacterized CD3 interaction partner that we provisionally termed CD3-associated protein (CD3AP). Initial experiments suggested that CD3AP is located in the endoplasmic reticulum and specifically binds to CD3ε, CD3δ, and CD3γ molecules. CD3AP silencing reduced the stability of these CD3 members, highlighting its ability to protect the CD3 chains from rapid degradation. The major objective of this proposal is the characterization of the molecular function and importance of CD3AP in immune cells. To this end, we will analyze its expression in various immune cell populations, dissect its mode of action using biochemical assays, and assess its importance for immune cell function in a CD3AP-deficient mouse model. The basic characterization of CD3AP functionality might improve our understanding of immune receptor assembly and uncover a so far unappreciated additional layer in the TCR quality control process.

• DFG Programme: Research Grants