CD5-mediated mTOR inhibition on T cells through binding of soluble CEACAM1

Introduction Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) controls immunity via self- or heteroligation. Its soluble isoform (sCC1) is elevated in sera of patients with obstructive and autoimmune liver diseases. In ConA-mediated hepatitis, Ceacam1-/- mice show exacerbation and persistence of hepatitis as a result of impaired Treg function and stability. T cell activation and Treg induction use the short CEACAM1 isoform (CECAM1-S), whereas its ITIM-bearing long isoform (CEACAM1-L) is required to impose T cell inhibition. Recently, we identified the Treg regulator CD5 as a novel binding partner for sCC1.

Objectives Confirm the role of sCC1-CD5 interaction in immune homeostasis.

Materials & Methods sCC1 was detected in serum samples of humans and mice by Western Blotting. LC-MS/MS identified sCC1-CD5 interactions. iTregs were induced by sCC1, sCD5, or CC1 and CD5 antibodies, or TGFb, and tested in suppression assays. Activation of signaling pathways critical for Treg induction (via pSTAT5, Foxp3, pSmad2/3, mTOR/pS6) were monitored in FACS and Western Blots.

Results sCC1 was detectable in sera of patients and mice with advanced PSC or ConA hepatitis. CEACAM1-CD5 interactions were confirmed and functionally tested in cell binding and Treg induction assays. sCC1 binding to activated T cells induced pSTAT5 and Foxp3 concomitant with reduction in mTOR activity. These effects were modulated by CD5 antibodies. sCC1-induced Tregs imposed suppression on T effector cells.

Conclusion Binding of sCC1 to activated T cells supports Treg induction by integrating CD5 mediated mTOR inhibition. Further experiments will reveal the role of CEACAM1-CD5 interaction in context of Treg homeostasis.

Publication History

Article published online:
26 January 2022