Nonobese diabetic (NOD) mice, a model of insulin-dependent diabetes mellitus, have a defect in natural killer (NK) cell-mediated functions. Here we show impairment in an activating receptor, NKG2D, in NOD NK cells. While resting NK cells from C57BL/6 and NOD mice expressed equivalent levels of NKG2D, upon activation NOD NK cells but not C57BL/6 NK cells expressed NKG2D ligands, which resulted in downmodulation of the receptor. NKG2D-dependent cytotoxicity and cytokine production were decreased because of receptor modulation, accounting for the dysfunction. Modulation of NKG2D was mostly dependent on the YxxM motif of DAP10, the NKG2D-associated adaptor that activates phosphoinositide 3 kinase. These results suggest that NK cells may be desensitized by exposure to NKG2D ligands.

TABLE OF CONTENTS Introduction 4 History and taxonomy of the genus Malassezia 5 Biological characteristics of Malassezia organisms 5 Structure 5 Reproduction 6 Biochemistry 6 Distribution of Malassezia organisms on the host 6 Immunological and epidermal responses to Malassezia organisms 7 The immune response to Malassezia organisms 7 Antigen release, penetration and presentation 8 Cell‐mediated immune responses 8 IgG, IgM and IgA responses to Malassezia organisms 9 IgE responses to Malassezia organisms 10 Mast cell responses 11 Epidermal responses associated with Malassezia dermatitis 12 Malassezia organisms as pathogens in humans and animals 13 Diseases associated with Malassezia spp. in humans 13 Pityriasis versicolor 13 Malassezia folliculitis 13 Seborrheic dermatitis and dandruff 14 Atopic dermatitis 14 Malassezia fungaemia 14 Diseases associated with Malassezia spp. in animals 15 Malassezia dermatitis in dogs 15 Predisposing factors for overgrowth of Malassezia pachydermatis 15 Pathogenesis 16 Clinical features 16 Diagnosis 17 Treatment 18 Conclusions 19 References 19

Prior studies have revealed that alternative mRNA splicing of the mouse NKG2D gene generates receptors that associate with either the DAP10 or DAP12 transmembrane adapter signaling proteins. We report that NKG2D function is normal in human patients lacking functional DAP12, indicating that DAP10 is sufficient for human NKG2D signal transduction. Further, we show that human NKG2D is incapable of associating with DAP12 and provide evidence that structural differences in the transmembrane of mouse and human NKG2D account for the species-specific difference for this immune receptor.