MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells

Abstract

The molecular basis of target cell recognition by CD3- natural killer (NK) cells is poorly understood, despite the ability of NK cells to lyse specific tumour cells. In general, target cell major histocompatibility complex (MHC) class I antigen expression correlates with resistance to NK cell-mediated lysis, possibly because NK cell-surface molecules engage MHC class I antigens and consequently deliver inhibitory signals. Natural killer cell allospecificity involves the MHC class I peptide-binding cleft, and further understanding of this allospecificity should provide insight into the molecular mechanisms of NK cell recognition. The Ly-49 cell surface molecular mechanisms of NK cell recognition. The Ly-49 cell surface molecule is expressed by 20% of CD3- NK cells in C57BL/6 mice (H-2b). Here we show that C57BL/6-derived, interleukin-2-activated NK cells expressing Ly-49 do not lyse target cells displaying H-2d or H-2k despite efficient spontaneous lysis by Ly-49- effector cells. This preferential resistance correlates with expression of target cell MHC class I antigens. Transfection and expression of H-2Dd, but not H-2Kd or H-2Ld, renders a susceptible target (H-2b) resistant to Ly-49+ effector cells. The transfected resistance is abrogated by monoclonal antibodies directed against Ly-49 or the alpha 1/alpha 2 domains of H-2Dd, suggesting that Ly-49 specifically interacts with the peptide-binding domains of the MHC class I alloantigen, H-2Dd. Inasmuch as Ly-49+ effector cells cannot be stimulated to lyse H-2Dd targets, our results indicate that NK cells may possess inhibitory receptors that specifically recognize MHC class I antigens.

Ly-49P Activates NK-Mediated Lysis by Recognizing H-2Dd 1

“…Collectively, Ly-49 molecules may contribute to a balance of positive and negative signals that control murine NK activities as well as those of certain subsets of T cells (3,7,8,9,18). Most studies of Ly-49 gene family members have used the B6 strain as a prototype.…”

“…Multiple Ly-49 receptors can be expressed simultaneously by an individual NK cell (5,6). A number of Ly-49 family members recognize class I MHC molecules, including Ly-49A, -C, and -G, and serve to inhibit NK function (7)(8)(9). Inhibitory Ly-49 receptors, as with CD94/NKG2A and a variety of Ig domain-containing receptors, inhibit NK function by recruiting the SH2 domain-containing tyrosine phosphatase SHP-1 3 to disrupt tyrosine kinase-dependent, membrane-proximal, signaling events (10).…”

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

“…Members of the human killer cell immunoglobulin receptor (KIR) family bind to different allotypes of HLA class Ia [13][14][15]. The corresponding function in mice is mediated by Ly49 receptors, which belong to a family of dimeric type II integral membrane proteins with a C-type (calcium-dependent) lectin-like domain [16][17][18][19]. Relevant receptors for this study are the Ly49C and I receptors, which are expressed by 35-60% of NK cells in the C57BL/6 (B6) strain and bind to H-2K b ligands expressed in the B6 mouse, and the Ly49G2 receptor, binding to H-2D d and H-2L d but lacking ligands in the B6 mouse [17][18][19][20].…”

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

“…13 Ly49 proteins are disulfide-linked homodimeric type II transmembrane receptors belonging to the C-type lectin receptor superfamily. 6 Ly49 genes are grouped in a gene cluster as part of the natural killer gene complex on chromosome 6.…”

“…18,19 The binding of inhibitory Ly49 receptors to MHC class I ligands results in an inhibition of cytotoxicity. 13,20 In contrast, NK killing can be triggered by activating Ly49 recognition of MHC class I expressed on target cells, suggesting a possible mechanism of NK cell-induced autoimmunity. 21,22 Furthermore, cross-linking of activating Ly49 molecules by specific monoclonal antibody (mAb) or MHC ligand results in cytokine production and intracellular calcium ion mobilization.…”