Expression of CD226 is associated to but not required for NK cell education

Abstract

DNAX accessory molecule-1 (DNAM-1, also known as CD226) is an activating receptor expressed on subsets of natural killer (NK) and T cells, interacts with its ligands CD155 or CD112, and has co-varied expression with inhibitory receptors. Since inhibitory receptors control NK-cell activation and are necessary for MHC-I-dependent education, we investigated whether DNAM-1 expression is also involved in NK-cell education. Here we show an MHC-I-dependent correlation between DNAM-1 expression and NK-cell education, and an association between DNAM-1 and NKG2A that occurs even in MHC class I deficient mice. DNAM-1 is expressed early during NK-cell development, precedes the expression of MHC-I-specific inhibitory receptors, and is modulated in an education-dependent fashion. Cd226−/− mice have missing self-responses and NK cells with a normal receptor repertoire. We propose a model in which NK-cell education prevents or delays downregulation of DNAM-1. This molecule endows educated NK cells with enhanced effector functions but is dispensable for education.

IL‐15 and CD155 expression regulate LAT expression in murine DNAM1+ NK cells, enhancing their effectors functions

“…It is also interesting to discuss our findings in the context of quantitative input received by NK cells during their education and IL‐15 priming by DCs . The quantity and the quality of the inhibitory Ly49 receptors for self MHC class I molecules, which guide NK cell education , correlate with the expression of the activating receptor DNAM1 . We hypothesized that educated DNAM1 + subsets are under tight regulation by different forces that control their auto‐reactivity including inhibitory interactions of Ly49 receptors with MHC‐I, activating interactions of DNAM1 with CD155, and IL‐15 signaling.…”

“…4C and E). Since DNAM1 expression levels have been previously shown to correlate with educated NK cells [6], we thus asked if the increase in effector functions in the DNAM1 + subset is dependent on NK cell education. Therefore, we stimulated educated NK cells isolated from WT mice or noneducated NK cells from MHC-I-KO mice, and compared effector functions between DNAM1 + and DNAM1 − subsets within each strain.…”

An update on potentials and promises of T cell co‐signaling molecules in transplantation

“…Primarily expressed on activated T cell and NK cells, DNAM-1 (CD226) has definite functions in differentiation of peripheral Treg and tolerance against allografts (Pende et al, 2005;Xu & Jin, 2010). Takenaka, Shibuya, & Shibuya, 2016;Wagner et al, 2017). Loss of DNAM-1 is associated with reduced severity of graft versus host disease (GVHD).…”

Blocking CD226 Promotes Allogeneic Transplant Immune Tolerance and Improves Skin Graft Survival by Increasing the Frequency of Regulatory T Cells in a Murine Model

“…The cytotoxic activity of CTL against target P815 cells was measured using a standard 4-h 51 Cr release assay as described previously [14]. Briefly, P815 cells were labeled with 3.7 × 10 6 Bq of sodium chromate (Na 2 51 CrO 4 ) (PerkinElmer) per 10 6 cells for 2 h at 37°C. CTL cells were incubated with these P815 cells in 96-well round-bottom plates for 4 h at 37°C and 5% CO 2 .…”

“…Similar to CD28 and CTLA-4, CD226 and TIGIT mainly share CD155 ligands, and CD112/CD113 in particular situations [4]. Interactions between CD226/TIGIT and its ligands are involved in many immunological activities, including NK cell education and cytotoxicity, naive T cell differentiation and proliferation, and platelet activation and aggregation [5,6].…”