CD96 Interaction with CD155 via Its First Ig-like Domain Is Modulated by Alternative Splicing or Mutations in Distal Ig-like Domains

Abstract

The adhesion receptor CD96 (TACTILE) is a transmembrane glycoprotein possessing three extracellular immunoglobulinlike domains. Among peripheral blood cells, CD96 is expressed on T cells as well as NK cells and a subpopulation of B cells. A possible function of this receptor in NK cell-mediated killing activities was suggested recently. Moreover, CD96 was described as a tumor marker for T-cell acute lymphoblastic leukemia and acute myeloid leukemia. CD96 binds to CD155 (poliovirus receptor) and nectin-1, an adhesion receptor related to CD155. Here we report that human but not mouse CD96 is expressed in two splice variants possessing either an I-like (variant 1) or V-like (variant 2) second domain. With the notable exception of an AML tumor sample, variant 2 predominates in all the CD96-expressing cell types and tissues examined. Using chimeric human/murine CD96 receptors, we show that the interaction with its ligands is mediated via the outermost V-like domain. In contrast to mouse, however, the binding of human CD96 to CD155 is sensitive to the characteristics of the two downstream domains. This is illustrated by a significantly weaker CD96/CD155 interaction mediated by variant 1 when compared with variant 2. Moreover, recent evidence suggested that mutations in human CD96 correlate with the occurrence of a rare form of trigonocephaly. One such mutation causing a single amino acid exchange in the third domain of human CD96 decreased the capacity of both variants to bind to CD155 considerably, suggesting that a CD96-driven adhesion to CD155 may be crucial in developmental processes.

Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy

“…Recently, CD96 was identifi ed, with TIGIT , as amongst the top 20 T cell-associated genes expressed in a screen of human lung squamous cell carcinoma samples ( 38 ). Human CD96 has been previously reported to play a role in facilitating NK-cell adhesion/cytotoxicity against CD155-expressing tumor cells ( 33,46 ). Whether anti-human CD96 mAbs can promote NK-cell/T-cell function remains to be established.…”

CD155 Is Involved in Negative Selection and Is Required To Retain Terminally Maturing CD8 T Cells in Thymus

“…CD155 belongs to the nectins, a family of Ig-like transmembrane proteins (21). All known physiological and pathogenic functions of CD155 are mediated via its outermost V-like domain harboring the docking epitopes for its known ligands: nectin-3, vitronectin, CD226, CD96, and poliovirus (22)(23)(24)(25)(26)(27)(28)(29). CD155 is involved in the establishment of adherens junctions between endothelial and epithelial cells (21) and was shown to influence cell motility, migration, and proliferation (30,31).…”

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

“…25 Prior studies of AS identified several genes mis-spliced in AML patients, including AML1, Gfi1b, CD96, survivin-2B, and GSK3beta. 8,15,21,[26][27][28][29] In our previous study, we used exon arrays to compare genome-wide gene-splicing events in AML vs normal CD34 1 cells and observed widespread differences. 30 Among the most frequently mis-spliced genes in AML patients were NOTCH2 and FLT3, and here we describe these events in detail.…”