Regulation of immune cell function and differentiation by the NKG2D receptor

Abstract

NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties, expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage. Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation.

Fig. 1

Coupling of the IL-15R and NKG2D signaling components in NK cells. The figure roughly summarizes interactions between signaling components of the IL-15R and NKG2D, which was proposed by Horng et al. [129]. Jak3, as a part of canonical IL-15R signaling pathway, is essential for the phosphorylation of DAP10. Activated DAP10 recruits PI3K and Grb2, which control proliferation, survival, and cytotoxicity of NK cells. DAP10 also associates with IL-15Rβ and -γ chains

Fig. 2

Comparison of Klrk1 ^−/− and Klrk1 ^∆/∆ mice. a Different mutations of the Klrk1 locus (upper row) in Klrk1 ^−/− (middle row) and Klrk1 ^∆/∆ (lower row) mice are shown. Klrk1 ^∆/∆ mice were obtained from the breeding of Klrk1 ^flox/flox and Cre deleter mice. b NKG2D expression on CD3⁻CD19⁻NK1.1⁺ cells isolated from the spleen of Klrk1 ^−/− (left panel) and Klrk1 ^∆/∆ (right panel) mice is shown

Fig. 3

Comparative analysis of NK cell phenotype and function between wild type, Klrk1 ^-/- and Klrk1 ^∆/∆ mice. a NK cells isolated from the spleens of 9 weeks old Klrk1 ^−/− and Klrk1 ^∆/∆ mice were analyzed by flow cytometry. Klrk ^+/+ littermates (B6) were used as controls. The data represent mean values of at least five mice per group. Error bars are indicated. b Indicated groups of Klrk1 ^−/−, Klrk1 ^∆/∆ and their littermate controls were infected intravenously with 5 × 10⁵ PFU of ∆m157 MCMV. The groups of mice were either NK cell depleted (PK136) or treated with PBS. Each symbol represents individual virus titers in indicated organs