NKG2D stimulated T-cell autoreactivity in giant cell arteritis and polymyalgia rheumatica

Objective To investigate functional expression of NKG(2)D on CD4 and CD8 T-cells in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). Methods Peripheral blood was drawn from patients with GCA (n=16), PMR (n=78) and healthy controls (HC, n=64). Tissue samples were obtained from GCA patients and controls. Proliferation and cytokine production assays were performed using CFSE and intracellular IFN- or TNF- staining, respectively, and flow cytometry analysis. Immunofluorescence and immunohistology were applied to analyse the presence of NKG(2)D-expressing T-cells and NKG(2)D-ligands in temporal arteries, respectively. mRNA levels of NKG(2)D-ligands were determined by RT-PCR. Results In both GCA and PMR patients, NKG(2)D was preferentially expressed on senescent CD4CD28(-) and CD8CD28(-), as well as on CD8CD28 T-cells. Frequencies of senescent T-cells were increased in GCA and PMR patients compared to HC. In GCA tissue samples, infiltrating T-cells were predominately CD28(-). NKG(2)D expressing T-cells concentrated around the vasa vasorum of the adventitia. Antigenic stimulation induced rapid up-regulation of NKG(2)D on CD4CD28(-) and CD4CD28 T-cells, whereas TNF- and interleukin-15 enhanced NKG(2)D expression on senescent CD4 and CD8 T-cells only. NKG(2)D cross-linkage augmented anti-CD3 triggered proliferation, IFN- and TNF- production of CD8 T-cells. In CD4CD28(-) T-cells, NKG(2)D ligation resulted in increased IFN- production only. NKG(2)D ligands were expressed in temporal arteries from GCA patients, particularly in the adventitial and medial layers of affected vessels. Conclusions NKG(2)D is functionally expressed on CD4CD28(-) and CD8 T-cells in GCA and PMR. NKG(2)D-ligands are present in temporal arteries and may co-stimulate NKG(2)D expressing T-cells.