PhD Defense: Natasja Nielsen

Regulatory natural killer cells in rheumatoid arthritis

Principal supervisor: Professor Niels Ødum

Evaluation committee:
Associate professor Anders Elm Pedersen, University of Copenhagen
Associate professor Veronique Braud, CNRS/UNSA
Associate professor Louise Berg, Karolinska Institutet

Rheumatoid arthritis is a chronic autoimmune disease that is characterized by joint inflammation and irreversible destruction of bone and cartilage. The inflamed joint is infiltrated by many immune cells, including CD4⁺ T cells and fibroblast-like synoviocytes (RA-FLS) that are known to play important roles in RA pathogenesis. Natural killer (NK) cells are an essential part of innate immunity, but numerous animal models of chronic inflammation have shown that NK cells can dampen autoimmunity by killing pro-inflammatory immune cells. Whether or not an NK cell is activated to kill depends on a balance of signals that are received through activating and inhibitory receptors on the cell surface. The purpose of this thesis was to study and characterize NK cell killing of activated CD4⁺ T cells and RA-FLS in vitro. We found that NK cells can kill both activated, but not resting, CD4⁺ T cells as well as RA-FLS, and that this is primarily mediated via the activating NK cell receptor NKG2D. Furthermore, we found that CD4⁺ T cells and RA-FLS are protected from NK cell lysis by expression of HLA-E, which binds the inhibitory NK cell receptor CD94-NKG2A. Blocking the interaction between HLA-E and CD94-NKG2A with an anti-NKG2A mAb enhances NK cell killing of both activated CD4⁺ T cells and RA-FLS in vitro. This suggests that blocking the interaction between an inhibitory receptor such as CD94-NKG2A and its ligand HLA-E can thus potentially be utilized as a novel NK cell-directed therapy to treat autoimmune diseases such as RA.