Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits proximal TCR signaling by targeting ZAP-70

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Long cytoplasmic tail (CT) isoforms of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) are expressed on activated human T cells.
• These CEACAM1 isoforms contain two ITIM motifs and are known to inhibit T cell receptor (TCR)/CD3 complex-initiated T cell responses, dependent on ITIMs and Src homology 2 domain-containing phosphatase 1 (SHP-1).

Purpose of the Study:

• To elucidate the mechanism by which CEACAM1 inhibits T cell responses.
• To investigate the roles of Lck, homophilic CEACAM1 binding, and SHP-1 recruitment in CEACAM1-mediated T cell inhibition.

Main Methods:

• Investigated the requirement of Src family kinase Lck and CEACAM1 homophilic binding for ITIM phosphorylation.
• Examined CEACAM1 association with and recruitment of SHP-1 to the TCR/CD3 complex.
• Assessed the impact on phosphorylation of CD3-zeta and ZAP-70 and downstream signaling.
• Evaluated the effect of SHP-1 extinction or CEACAM1 homophilic binding blockade on T cell cytolytic function.

Main Results:

• Src family kinase Lck and CEACAM1 homophilic binding are essential for ITIM phosphorylation, a prerequisite for SHP-1 association.
• CEACAM1 associates with and recruits SHP-1 to the TCR/CD3 complex.
• This recruitment leads to decreased phosphorylation of CD3-zeta and ZAP-70, subsequently reducing downstream activation.
• Blocking SHP-1 or CEACAM1 homophilic binding enhances TCR/CD3-initiated cytolytic function.

Conclusions:

• Long CT CEACAM1 isoforms induce T cell inhibition by targeting proximal signaling events downstream of the TCR/CD3 complex.
• The mechanism involves SHP-1 recruitment to the TCR/CD3 complex, impairing ZAP-70 activation.
• CEACAM1-mediated inhibition of T cell function is physiologically relevant and can be modulated by targeting CEACAM1 homophilic binding or SHP-1 activity.