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2017-Bernson-Thesis

Abstract
Natural killer (NK) cells are lymphocytes endowed with cytotoxicity against aberrant
cells, including transformed and virus-infected cells. NK cell function is dictated by a
fine-tuned interplay between activating and inhibitory receptors expressed on the NK
cell surface. While the different activating receptors interact with unique ligands present
on healthy or transformed cells, inhibitory NKG2A and killer immunoglobulin-like
receptors (KIRs) invariably recognize HLA class I molecules. The purpose of this thesis
was to elucidate how interactions between inhibitory NK cell receptors and HLA class I
impact on anti-leukemic functions of NK cells and on NK cell-mediated termination of
inflammation. In a phase IV trial, 81 AML patients received histamine dihydrochloride
and low-dose interleukin-2 (HDC/IL-2) for the prevention of recurrence of leukemia
after the completion of chemotherapy. The trial comprised immunophenotyping of
serial blood samples along with KIR/HLA genotyping and assessment of
cytomegalovirus (CMV) serostatus. Results from papers I and II imply a beneficial role
of NK cell subsets that are less inhibited by HLA while prior CMV infection, which
promotes the expression of additional KIRs, impacted negatively on relapse risk and
survival. Additionally, a single nucleotide polymorphism in HLA-B that dictates NK cell
inhibition to be preferentially mediated by NKG2A impacted positively on outcome in
this trial (paper III). The relevance of the interplay between activating and HLAmediated
inhibitory signaling was further illustrated in a non-malignant setting in paper
IV, where modulation of NK cell receptor ligands expressed by inflammatory
neutrophils was associated with enhanced susceptibility to NK cell cytotoxicity. In
conclusion, these studies support i) that low-grade KIR-mediated inhibition of NK cells
is relevant for the benefit of relapse-preventive immunotherapy in AML and ii) that NK
cells participate in the resolution of inflammation.