Activation-Induced Expression of Carcinoembryonic Antigen-Cell Adhesion Molecule 1 Regulates Mouse T Lymphocyte Function

Abstract

Carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) consists of highly related homologs in humans and rodents that are characterized by significant alternate splicing generating isoforms capable of negative intracellular signaling by virtue of two immunoreceptor tyrosine-based inhibition motifs in its cytoplasmic (cyt) tail. Although human T cells have been recently observed to express CEACAM1, the expression and function of CEACAM1 in mouse T cells have not been defined. Although resting mouse spleen T cells exhibited no evidence of CEACAM1 on the cell surface, CEACAM1 was rapidly up-regulated on CD4+ and CD8+ T cells after activation with either Con A or anti-CD3 without a requirement for either de novo transcription or translation due to the fact that CEACAM1 was present intracellularly before activation. Using a GST-CEACAM1-cytoplasmic tail fusion protein, it was shown that the cytoplasmic tail of CEACAM1 bound the src homology domain-containing phosphatase 1 and adaptor protein 1 complex in its phosphorylated and nonphosphorylated states, respectively. CEACAM1 ligation with an anti-CEACAM1 mAb resulted in inhibition of an allogeneic MLR and anti-CD3 plus anti-CD28 Ab-induced proliferation of spleen T cells in vitro and inhibition of a delayed-type hypersensitivity response to oxazolone in vivo. Inhibition of the delayed-type hypersensitivity response required that the anti-CEACAM1-specific mAb be present at the time of T cell sensitization. These studies support a role for CEACAM1 as a novel class of immunoreceptor tyrosine-based inhibition motif-bearing regulatory molecules on T cells that are active during early phases of the immune response in mice.

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

“…Previous work noted that CEACAM1 is localized within intracellular granules in unstimulated murine T cells yet appears on the cell surface upon engagement of the TCR (38). We observed that CEACAM1 is also mobilized to the surface of activated human primary CD4 ϩ T cells upon exposure to either Abs that ligate the TCR or infection by N. gonorrhoeae.…”

“…The intracellular storage of these coinhibitory receptors presumably facilitates an early sensitivity to TCR-dependent activating signals, with subsequent diminution as CEACAM1 is delivered to the cell surface. (60) are not phosphorylated (38). This exposes binding motifs for the clathrin adaptor protein AP-1 (38) and AP-2 (24), which promote receptor internalization.…”

“…Because CEACAM1 ITIMs are a substrate for activated Src family kinases (61), the limited CEACAM1 present at the T cell surface may become transiently phosphorylated. The newly generated phosphotyrosine residues preclude AP-1 and AP-2 recognition of the CEACAM1 ITIM (24,38), delaying its recovery from the cell surface. C, During T cell infection by N. gonorrhoeae, Opa CEA binding retains CEACAM1 at the cell surface due to the lymphocyte's inability to engulf the adherent bacteria.…”

“…Past work suggests that normal cycling of CEACAM1 from the cell surface is mediated by the clathrin-associated adaptor protein complexes AP-1 (38) and/or AP-2 (24), which specifically bind YXX motifs within the CEACAM1 ITIMs. Phosphorylation of tyrosine residues within the CEACAM1 cytoplasmic domain precludes AP-1 and AP-2 binding, altering the equilibrium of receptor recycling such that CEACAM1 accumulates at the T cell surface.…”

CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo

“…35 In contrast, in mouse spleen T lymphocytes, CEACAM1 was not present on the surface of resting cells but was rapidly up-regulated on CD4 ϩ and CD8 ϩ T cells after activation with either Con A or anti-CD3 stimulation. 36 Overall, these studies in leukocytes are somewhat different from the CEACAM1 expression profile that we have observed in murine and human platelets with moderate basal expression on the surface of resting platelets with an intracellular pool evident (Figure 1A-D). This difference Figure 5.…”