In a recent study published in PNAS, a research group led by Prof. George Fu Gao from Institute of Microbiology of Chinese Academy of Sciences reported the structures of human and mouse CD226, both of which present a unique side-by-side arrangement pattern of two tandem immunoglobulin V-set (IgV) domains.

This arrangement mode is distinct from the conventional head-to-tail organizing mode, as shown in the structure of CD155, of all the known Ig-like superfamily members. The only exception they found is VCBP3, an Ig-like molecule in amphioxus that diverged early in phylogeny. This finding might give a hint of the evolution of Ig-like molecules.

Researchers then systematically analyzed the binding mechanism between CD226 and CD155 by determining a hybrid complex structure of mouse CD226 bound to CD155, which revealed a conserved binding interface within the first domain of CD226 (D1).

Intriguingly, they found that the second domain of CD226 (D2) both provides structural supports for the unique architecture of CD226 and forms direct interactions with CD155. This distinct binding model is unique in TIGIT-CD226-CD96 paired receptor family.

Taken together, the structural and functional data of this study broadened the knowledge of the recognition between NK cell receptors and the nectin/Necl family ligands, and provided molecular basis for the development of CD226-targeted antitumor immunotherapy.

NK cells are important component of innate immunity for the roles in responding early to viral infection and malignancies by cell-mediated cytotoxicity. They also contribute to activating and reshaping the adaptive immune responses via secreted cytokines.

The study was funded by National Natural Science Foundation of China, Strategic Priority Research Program of the Chinese Academy of Sciences, and National Postdoctoral Program for Innovative Talents.