DNAM-1

DNAM-1 (CD226) is the acronym for "DNX-Accessory Molecule-1". DNAM-1 is a cell surface glycoprotein that functions as an adhesion molecule. After communicating with activating receptors, DNAM-1 controls interferon-γ production against a variety of pathogens via NK cell cytotoxicity (Martinet L et al. 2015b). Its ligands CD112 and CD155 have been described in various pathological conditions, and further evidence suggests that their expression is regulated by cellular stress.

DNAM-1 binds to other receptors besides CD112 and CD155 that modulate NK cell functions such as:

CD96 (TACTILE) and

TIGIT (WUCAM, VSTM3).

NK cells are found in various stages of maturation in tissues such as spleen, lymph nodes, liver and lung. They show a differentiated reactivity to cytokines and effectors. Their reactivity was attributed to the different maturation state. The functional heterogeneity of NK cells of similar maturation was shown to exist on the differential expressivity of DNAM-1 (Martinet L et al. 2015).

DNAM-1 expression is uniform on NK cell progenitor cells. However, it is downregulated as NK cells mature, giving rise to DNAM-1+ and DNAM-1- NK cells in the periphery. The ratio of DNAM-1+ NK cells/ DNAM-1- NK cells decreases from birth. The DNAM-1 NK cells are apparently unable to return to a DNAM-1+ state.

DNAM-1 expression is strongly linked to effector functions of NK cells, with DNAM-1+ NK cells producing significantly more IFN-γ, IL-6, CCL5 and GM-CSF, but less MIP1α/β than their DNAM-1- NK cell counterparts after stimulation with IL-12 and IL-18 ((Martinet L et al. 2015). DNAM-1+ NK cells also contribute to greater IFN-γ secretion in vivo than DNAM-1- NK cells and are able to suppress tumor growth and metastasis more effectively in vivo.

DNAM-1 expression did not correlate with other known markers of NK cell maturation such as KLRG1 (Huntington ND et al. 2007) and CD27/CD11b (Hayakawa Yet al. 2006), with both KLRG1+ and CD27/CD11b NK cell subsets expressing similar proportions of DNAM-1+ and DNAM-1- NK cells.

1. Georgiev HG et al (2018) Coming of Age: CD96 Emerges as Modulator of Immune Responses. Front. Immunol 9: 1072.

2. Hayakawa Yet al. (2006) CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J Immunol 176:1517-1524.

3. Huntington ND et al (2007) NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J Immunol 1784: 764-770.

4. Martinet L et al (2015a) DNAM-1 expression marks an alternative program of NK cell maturation. Cell Rep 11:85-97.

5. Martinet L et al (2015b) Balancing natural killer cell activation through paired receptors. Nat Rev Immunol 15:243-254.