Biological function of the soluble CEACAM1 protein and implications in TAP2‐deficient patients

Abstract

Interactions of natural killer (NK) cells with MHC class I proteins provide the main inhibitory signals controlling NK killing activity. It is therefore surprising to learn that TAP2-deficient patients suffer from autoimmune manifestations only occasionally in later stages of life. We have previously described that the CEACAM1-mediated inhibitory mechanism of NK cytotoxicity plays a major role in controlling NK autoreactivity in three newly identified TAP2-deficient siblings. This novel mechanism probably compensates for the lack of MHC class Imediated inhibition. The CEACAM1 protein can also be present in a soluble form and the biological function of the soluble form of CEACAM1 with regard to NK cells has not been investigated. Here we show that the homophilic CEACAM1 interactions are abrogated in the presence of soluble CEACAM1 protein in a dose-dependent manner. Importantly, the amounts of soluble CEACAM1 protein detected in sera derived from the TAP2-deficient patients were dramatically reduced as compared to healthy controls. This dramatic reduction does not depend on the membrane-bound metalloproteinase activity. Thus, the expression of CEACAM1 and the absence of soluble CEACAM1 observed in the TAP2-deficient patients practically maximize the inhibitory effect and probably help to minimize autoimmunity in these patients.

Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions

“…Indeed, a strong association of CEACAM1 expression on primary cutaneous melanoma lesions with the development of metastatic disease and poor survival was recently reported (27). In addition, we have recently demonstrated the cardinal role of CEACAM1-mediated inhibition in maintaining NK self-tolerance in TAP2-deficient patients (31,32). Other reports (33,34) have shown that CEACAM1 engagement either by TCR cross-linking with mAb or by Neisseria gonorrhoeae Opa proteins inhibits T cell proliferation.…”

“…2). The anti-CEACAM Kat4c mAb is agonistic when bound either to a solid phase (32) or to Fc receptors of P815 cells (29). Thus, activation of TIL killing activity is reduced if CEACAM1 is engaged concomitantly to CD3.…”

“…Mouse BW cells were stably transfected with a chimeric molecule composed of the extracellular portion of CEACAM1 fused to mouse -chain, as described previously (30). Engagement of CEACAM1 leads to the secretion of mouse IL-2, mediated by the -chain, in a dose-dependent manner (32). The amounts of IL-2 in the culture supernatants were evaluated with standard sandwich ELISA.…”

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 + T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

“…Soluble receptors have been reported for multiple coinhibitory molecules, including LAG-3 and CEACAM1 (9,15,16). The mechanisms for soluble receptor production are different for LAG-3 and CEACAM1.…”

Reduced KIR2DL1 Recognition of MHC Class I Molecules Presenting Phosphorylated Peptides

“…In contrast, the killing of normal cells is inhibited by a complex set of inhibitory receptors that are present on NK cells and recognize MHC class I proteins on the cell surface of the target cells (3)(4)(5). In addition, the killing of NK cells is also inhibited in a class I-independent manner by receptors such as the leukocyte-associated Ig-like receptor (6), carcinoembryonic Ag cell adhesion molecule 1 (7)(8)(9), and sometimes even 2B4 (10,11).…”