A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions

Abstract

Immunoglobulin superfamily (IgSF) members account for a large proportion of cell adhesion molecules that perform important immunological functions, including recognizing a variety of counterpart molecules on the cell surface or extracellular matrix. The findings that CD155/poliovirus receptor (PVR) and CD112/nectin-2 are the ligands for CD226/platelet and T-cell activation antigen 1 (PTA1)/DNAX accessory molecular-1 (DNAM-1), CD96/tactile and Washington University cell adhesion molecule (WUCAM) and that CD226 is physically and functionally associated with lymphocyte function-associated antigen-1 (LFA-1) on natural killer (NK) and activated T cells have largely expanded our knowledge about the functions of CD226, CD96, WUCAM and LFA-1 and their respective ligands, CD155, CD112, intercellular adhesion molecule (ICAM)-1 and junctional adhesion molecule (JAM)-1. The interactions of these receptors and their ligands are involved in many key functions of immune cells including naive T cells, cytotoxic T cells, NK cells, NK T cells, monocytes, dendritic cells, mast cells and platelets/megakaryocytes.

Figure 1

Comparison of the protein sequences among human, gibbon, monkey and mouse CD226. The predicated signal peptide (Met⁻¹⁸ to Cys⁻¹) and transmembrane sequences (Leu²⁵¹ to Leu²⁶⁵ for human and gibbon CD226, Arg²⁵¹ to Leu²⁶⁵ for monkey CD226 and Leu²⁵³ to Tyr²⁶⁷ for mouse CD226) are underlined. The conserved cysteines (Cys, Cys¹⁰⁸, Cys¹⁵² and Cys²²² for human, gibbon and monkey CD226, and Cys, Cys¹⁰⁹, Cys¹⁵³ and Cys²²⁴ for mouse CD226) predicated to form the disulfide bonds that stabilize the two V-like domains are boxed. The key phosphorylation sites (Tyr³²² and Ser³²⁹ for human, gibbon and monkey CD226, and Tyr³¹⁹ and Ser³²⁶ for mouse CD226) are indicated by ♦ and *, respectively. The murine CD226 ORF encodes a protein of 333 amino acids, which is 3 amino acid shorter than that of human CD226. Compared with human CD226, mouse CD226 has 53% identity at the amino acid level, while human, gibbon and monkey CD226 protein have the same length of 336 amino acid residues and their CD226 sequences have 93–95% amino acid identity.

Figure 2

Dendrogram analysis of IgSF member V domains. The dendrogram of immunoglobulin superfamily member V domains was analyzed by ClustalX software. Analysis results showed that the first V domains of CD226 and CD96 have the closest relationship with respect to sequence similarity comparison. The V domains of nectin-2/CD112 and PVR/CD155 have the highest homology. C1L, C1-like; CNS, central nervous system; DC, dendritic cell; ICAM-1, intercellular adhesion molecule-1; IgSF, immunoglobulin superfamily; JAM-1, junctional adhesion molecule-1; LFA-1, lymphocyte function-associated antigen-1; NK, natural killer; NKT, natural killer T cell; PTA1, platelet and T-cell activation antigen 1; PVR, poliovirus receptor; WUCAM, Washington University cell adhesion molecule.

Figure 3

Cross-recognition between ligands CD155, CD112, CD54, CD321 and their receptors CD226, CD96, LFA-1 and WUCAM. Tactile/CD96, PTA1/DNAM-1/CD226, LFA-1 and WUCAM are expressed on T cells, NK cells, NK T cells, monocytes, megakaryocytes or platelets, while their ligands PVR/CD155, nectin-2/CD112, ICAM-1/CD54 and JAM-1/CD321 are expressed on endothelial cells and target cells such as tumor cells. Both PVR/CD155 and JAM-1/CD321 are associated with the αvβ3 integrin. PTA1/DNAM-1/CD226 recognizes ligands PVR/CD155 and nectin-2/CD112, while tactile/CD96 recognizes PVR/CD155 but not nectin-2/CD112. LFA-1/αLβ2 physically and functionally associated with CD226 bound to ICAM-1/CD54 and JAM-1/CD321. C1L, C1-like; DNAM-1, DNAX accessory molecular-1; HSV, herpes simplex virus; ICAM-1, intercellular adhesion molecule-1; JAM-1, junctional adhesion molecule-1; LFA-1, lymphocyte function-associated antigen-1; NK, natural killer; PTA1, platelet and T-cell activation antigen 1; PVR, poliovirus receptor; WUCAM, Washington University cell adhesion molecule.

Figure 4

CD155, CD112, CD321 and CD54 serve as virus receptors. CD155 and CD112, the ligands for receptors CD226 and CD96, and CD54 and CD321, the ligands for LFA-1, which is closely associated with CD226, serve as receptors for Poliovirus, herpes simplex virus (HSV) and Rhinovirus and Reovirus, respectively. In addition, human cytomegalovirus (HCMV) viral product UL141 can block CD155, which may contribute to the protection of virus-infected cells from NK-mediated attack. CTL, cytotoxic lymphocyte; DC, dendritic cell; iDC, immature DC; Ig, immunoglobulin; JAM-1, junctional adhesion molecule-1; LFA-1, lymphocyte function-associated antigen-1; NK, natural killer; TCR, T-cell receptor.

Figure 5

The interactions of CD226 and CD96 with their ligands participate in multiple immunological functions. Detailed explanations are described in Table 1. CTL, cytotoxic lymphocyte; DC, dendritic cell; NK, natural killer.