I. Identification of factors that shape human NK cell repertoires

HLA class I-specific receptors are expressed on natural killer (NK) cells in a clonally-distributed fashion and together constitute the so-called NK cell repertoire. We have recently shown that the NK cell repertoire goes through a major transition from birth to adulthood with changes in the contribution of KIR and NKG2A receptors to recognition of autologous HLA class I ligands. We want to understand how NK cells adapt and still remain tolerant during the transition from a naïve, neonatal to an antigen-experienced state and how that affects recognition of tumor and virus-infected target cells. Specific subprojects are:

       ·     Development of neonatal NK cell repertoires

       ·      Influence of HLA class I and KIR haplotype on NK repertoire formation

       ·      Sequential acquisition of KIR receptors during NK cell development

       ·      Virus-induced changes in NK cell repertoires

II. Epigenetic regulation of clonal KIR expression

The KIR gene family is regulated in a special way that ensures that all possible combinations of KIR are expressed on different NK cells. We have previously shown that DNA methylation is involved in regulation of KIR expression. We would like to understand how KIR genes get demethylated during NK cell development. In this context we have projects addressing:

       ·      the role of the recently discovered DNA hydroxymethylation

       ·      contribution of histone modifications  

       ·      influence of microRNAs  

III. Clinical role of NK cells in leukemia and solid tumors

NK cells are key players of the natural immune system that are able to effectively recognize malignant cells. We want to understand how individual differences in KIR genes and receptor repertoires affect tumor recognition. Moreover, we would like to identify, isolate, and expand human tumor-specific NK cells to generate effective products for NK cell-based immunotherapy. Subprojects are:

     ·      Association of KIR gene polymorphism with leukemia development

     ·      Role of NK cells in recognition of circulating tumor cells

     ·      Development of  protocols to enrich tumor-specific NK cells