SHP1 Phosphatase-Dependent T Cell Inhibition by CEACAM1 Adhesion Molecule Isoforms

Abstract

T cell activation through the T cell receptor (TCR) is subsequently modified by secondary signals that are either stimulatory or inhibitory. We show that CEACAM1 adhesion molecule isoforms containing a long cytoplasmic domain inhibited multiple T cell functions as a consequence of TCR ligation. Overexpression of CEACAM1 resulted in decreased proliferation, allogeneic reactivity, and cytokine production in vitro and delayed type hypersensitivity and inflammatory bowel disease in mouse models in vivo. Conditioned deletion of CEACAM1 in T cells caused increased TCR-CD3 complex signaling. This T cell regulation was dependent upon the presence of immunoreceptor tyrosine-based inhibition motifs (ITIM) within the cytoplasmic domain of CEACAM1 and the Src homology 2 domain-containing protein tyrosine-phosphatase 1 (SHP1) in the T cell. Thus, CEACAM1 overexpression or deletion in T cells resulted in T cell inhibition or activation, respectively, revealing a role for CEACAM1 as a class of inhibitory receptors potentially amenable to therapeutic manipulation.

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

“…16 This finding supports the concept in immunologic systems that SHP-1 protein-tyrosine phosphatase acts as a negative regulator. 33 However, in collagen-GPVI-mediated platelet responses, SHP-1 has been proposed to act as a positive regulator.…”

“…14,15 Based on recent studies in T cells, CEACAM1 functions as a negative regulator via its recruitment and activation of SHP-1 protein-tyrosine phosphatase. 16 However, little is known about the presence and functional role of CEACAM1 in regulating platelet-collagen interactions and thrombus formation in vitro and in vivo. The only exception was a report by Hansson et al in 1990 that suggested that C-CAM (old terminology for CEACAM1) was present in the intracellular compartment of rat platelets.…”

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

“…Moreover, we found that an IFNg-driven upregulation of CEACAM1 on melanoma cells surviving TIL-mediated attack renders them even more resistant (20). The inhibitory effect of CEA-CAM1 is exerted by the recruitment of SHP-1 phosphatase to the cytosolic ITIM sequences (21). Lymphocytes express only the CEACAM1 isoform that bears a long cytosolic tail (22), and there is a similar dominance of the long isoform in melanoma cells (20).…”

CEACAM1 : modulateur central du métabolisme, de la progression tumorale,de l’angiogenèse et de l’immunité

“…Premièrement, CEACAM1 est rapidement surexprimée à la surface des lymphocytes T après activation du complexe TCR par des cytokines telles l'IL-2 [27]. Les lymphocytes T présents dans le côlon surexpriment également CEACAM1 lors de l'inflammation de l'intestin [28].…”

“…ainsi qu'une augmentation de la production d'IL-2 et d'interféron γ. CEACAM1-L surexprimée à la surface des lymphocytes T inhibe la capacité qu'ont les cellules T naïves d'induire l'inflammation du côlon [27]. Ces observations pourraient avoir une traduction thérapeutique dans le traitement des maladies inflammatoires de l'intestin.…”