Alexander B. H. Bakker

Retinoic Acid Early Inducible Genes Define a Ligand Family for the Activating NKG2D Receptor in Mice

Here we describe a family of GPI-anchored cell surface proteins that function as ligands for the mouse activating NKG2D receptor. These molecules are encoded by the retinoic acid early inducible (RAE-1) and H60 minor histocompatibility antigen genes on mouse chromosome 10 and show weak homology with MHC class I. Expression of the NKG2D ligands is low or absent on normal, adult tissues; however, they are constitutively expressed on some tumors and upregulated by retinoic acid. Ectopic expression of RAE-1 and H60 confers target susceptibility to NK cell attack. These studies identify a family of ligands for the activating NKG2D receptor on NK and T cells, which may play an important role in innate and adaptive immunity.

Loss-of-function mutations in TYROBP ( DAP12 ) result in a presenile dementia with bone cysts

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2×10−6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

DAP12-Deficient Mice Fail to Develop Autoimmunity Due to Impaired Antigen Priming

DAP12 is an ITAM-bearing membrane adaptor molecule implicated in the activation of NK and myeloid cells. In mice rendered DAP12 deficient by targeted gene disruption, lymphoid and myeloid development was apparently normal, although the activating Ly49 receptors on NK cells were downregulated and nonfunctional. To analyze the consequences of DAP12 deficiency in vivo, we examined the susceptibility of DAP12-/- mice to experimental autoimmune encephalomyelitis (EAE). DAP12-/- mice were resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide. Resistance was associated with a strongly diminished production of IFNgamma by myelin-reactive CD4+ T cells due to inadequate T cell priming in vivo. These data suggest that DAP12 signaling may be required for optimal antigen-presenting cell (APC) function or inflammation.

The ITAM-bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function

DAP12, an ITAM-bearing transmembrane adaptor protein, associates non-covalently with receptors in natural killer (NK) and myeloid cells, and provides signaling function via the Syk and ZAP-70 tyrosine kinase activation pathways. Humans and mice lacking DAP12 (DAP12(-/-)) show normal development of hematopoietic cells. However, DAP12(-/-) humans develop presenile dementia and bone cysts, and DAP12(-/-) mice show impaired immune responses.

NK cell activation: distinct stimulatory pathways counterbalancing inhibitory signals

A delicate balance between positive and negative signals regulates NK cell effector function. Activation of NK cells may be initiated by the triggering of multiple adhesion or costimulatory molecules, and can be counterbalanced by inhibitory signals induced by receptors for MHC class I. A common pathway of inhibitory signaling is provided by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic domains of these receptors which mediate the recruitment of SH2 domain-bearing tyrosine phosphate-1 (SHP-1). In contrast to the extensive progress that has been made regarding the negative regulation of NK cell function, our knowledge of the signals that activate NK cells is still poor. Recent studies of the activating receptor complexes have shed new light on the induction of NK cell effector function. Several NK receptors using novel adaptors with immunoreceptor tyrosine-based activation motifs (ITAMs) and with PI 3-kinase recruiting motifs have been implicated in NK cell stimulation.

Dendritic cells in immune response induction.

The study of dendritic cells (DCs) has seen a rapid expansion in recent years, and their importance within the immune system is now widely recognized. Along with B lymphocytes and mononuclear phagocytes, DCs make up what are known as the professional antigen‐presenting cells (APCs). These are cells which are capable of highly efficiently presenting antigens to the immune system in the context of both major histocompatibility complex class I and class II molecules. What makes DCs stand out from other professional APCs, however, is their seemingly unique ability to present antigen to T lymphocytes which have had no previous contact with antigen. This gives DCs a central role in the initiation of immune responses, and creates possibilities for their exploitation in the development of therapeutic strategies against tumors and other diseases.