The Cell-Cell Adhesion Molecule Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1 Inhibits IL-2 Production and Proliferation in Human T Cells by Association with Src Homology Protein-1 and Down-Regulates IL-2 Receptor

Abstract

The cell adhesion molecule, carcinoembryonic Ag-related cellular adhesion molecule 1, shown by others to both activate and inhibit T cell proliferation, exhibits a reciprocal relationship to IL-2R expression over the time course of activation of PBMCs, and upon Ab ligation, inhibits both the production of IL-2 and cell proliferation. Carcinoembryonic Ag-related cellular adhesion molecule 1 associates with CD3 and is found in lipid rafts of PBMCs, is phosphorylated on the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of the -4L isoform, and associates with Src homology protein-1, providing an explanation for its inhibitory activity. When the ITIM-containing -4L and non-ITIM-containing -4S isoforms are transfected into Jurkat cells that produce, but do not depend on IL-2 for growth, both IL-2 production and cell proliferation are differentially inhibited, demonstrating that the two isoforms signal via different pathways. When the two isoforms are transfected into Kit-225 cells that depend on IL-2 for growth, IL-2Rβ and γ, but not α subunits are down-regulated, and the -4L, but not the -4S isoform inhibits cell proliferation by 6-fold in an IL-2 dose-response study.

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

“…The marked reduction in phosphotyrosine-dependent signals immediately downstream of the TCR is consistent with effect of CEACAM1 homophilic and/or heterophilic binding (3,(32)(33)(34)38). In the context of neisserial infections, the reduced number of activated T cells could also explain the defect in humoral memory elicited during N. gonorrhoeae infections in humans (4,42).…”

“…For example, the lytic activity of NK cells is hindered by CEACAM1 homophilic binding (29,30), and the cytoplasmic domain of CEACAM1 itself inhibits BCR-induced Ca ϩ mobilization in recombinant chicken DT40 B cells (31). Although immortalized T cell lines have down-regulated CEACAM1 expression, studies performed with transfected Jurkat CD4 ϩ T cells indicate that the cytoplasmic domain of CEACAM1 is required for the inhibition of T cell proliferation and IL-2 expression (32,33). These inhibitory effects were apparent upon increased homophilic binding caused by CEACAM1 overexpression or CEACAM1 ligation by Abs and require the tyrosine residues within the ITIMs in the CEACAM1 cytoplasmic domain (32,33).…”

“…Neisserial binding to CEACAM1 has been reported to suppress SHP-1 activity in monocytes (39). Yet, in the context of a T cell, studies done with the human Jurkat CD4 ϩ cell line and mouse primary T lymphocytes indicate that CEACAM1 specifically recruits SHP-1 (32,38) and that the coinhibitory function of CEACAM1 is attributable to SHP-1 (33,34). Herein, we established that N. gonorrhoeae expressing Opa CEA promote a CEACAM1-dependent recruitment of both SHP-1 and SHP-2 as the bacteria adhere to T cells and that both phosphatases are activated upon neisserial binding.…”

“…Although immortalized T cell lines have down-regulated CEACAM1 expression, studies performed with transfected Jurkat CD4 ϩ T cells indicate that the cytoplasmic domain of CEACAM1 is required for the inhibition of T cell proliferation and IL-2 expression (32,33). These inhibitory effects were apparent upon increased homophilic binding caused by CEACAM1 overexpression or CEACAM1 ligation by Abs and require the tyrosine residues within the ITIMs in the CEACAM1 cytoplasmic domain (32,33). Studies performed in mice also demonstrate that CEACAM1-specific agonists inhibit Th1 and Th2 cytokine expression and immune-mediated delayed type hypersensitivity and inflammatory bowel disease in vivo (34).…”

Rac1 Protein Regulates Glycogen Phosphorylase Activation and Controls Interleukin (IL)-2-dependent T Cell Proliferation

“…Agonists and Inhibitors-Kit 225 cells were maintained in the absence of IL-2 for 48 h and subsequently stimulated with 500 units/ml IL-2 at 37°C as indicated under "Results" (33). In some experiments, Kit 225 cells were pretreated with 50 M NCS23766 (Rac1 inhibitor) (34) or 10 M glycogen phosphorylase inhibitor (GPI) (35) for 16 h and with 50 M H89 (PKA inhibitor) (36) for 1 h prior to IL-2 or 10 M forskolin (37) stimulation.…”