Natural Killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood major lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 35 parameters, including 28 NK cell receptors, on peripheral blood NK cells from five sets of monozygotic twins and twelve unrelated donors of defined HLA and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6,000-30,000 phenotypic populations within an individual and >100,000 phenotypes in this population. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors, while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation.

Background Prior studies have presented contradictory results after analyzing associations between donor and recipient sex on survival after heart transplantation and causes of death such as acute rejection (AR) and cardiac allograft vasculopathy (CAV). We used the ISHLT Registry, the largest repository of heart transplant outcomes worldwide, to comprehensively address these questions. Methods We studied 60,584 adult recipients of heart transplants performed between 1990 and 2008. Outcomes of interest were overall survival, death-censored allograft survival, AR, and CAV, which were studied using regression models. To assess whether donor: recipient sex mismatch affected outcomes, the experience of male recipients with female versus male donors was compared to that of female recipients with female versus male donors through inclusion of an interaction term between donor and recipient sex. Results Significant differences were observed between male and female recipients in overall survival and death-censored allograft survival for female versus male donors. Male recipients of female allografts had a 10% increase in adjusted mortality relative to male recipients of male allografts, while female recipients of female allografts had a 10% decrease in adjusted mortality relative to female recipients of male allografts (p<0.0001). Findings were similar for death-censored allograft survival. There were no significant differences in the effect of donor sex on AR or CAV between male and female recipients. Conclusions Analysis of the ISHLT data set has demonstrated a strong association between donor: recipient sex-mismatch and reduced survival after heart transplantation.

Background-Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that causes blindness, stroke, and aortic aneurysm. CD4 T cells are key pathogenic regulators, instructed by vessel wall dendritic cells to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell-T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids. Methods and Results-Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain in wall-infiltrating T cells indicated ongoing NOTCH pathway activation in large-vessel vasculitis. NOTCH activation did not occur in small-vessel vasculitis affecting branches of the vasa vasorum tree. We devised 2 strategies to block NOTCH pathway activation: ␥-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc.In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses. Conclusions-Blocking