Expansion of circulating NKG2D+ effector memory T-cells and expression of NKG2D-ligand MIC in granulomaous lesions in Wegenerʹs granulomatosis

Expansion of circulating CD28− T-cells reminiscent of effector memory T-cells (TEM) has been reported in Wegenerʹs granulomatosis (WG) recently. To investigate the role of TEM in WG, we analyzed the expression of the activating NK-receptor NKG2D and its ligand MIC on circulating TEM and in granulomatous lesions, respectively. NKG2D was anomalously expressed and preferentially detected on circulating CD4+CD28- TEM in WG. Compared to healthy controls, TEM display a more activated phenotype potentially favoring unbalanced proinflammatory responses in WG. Cluster-like formations of “Wegenerʹs autoantigen” PR3 were surrounded by NKG2D+ and NKG2D−ligand MIC+ cells in WG-granulomata, but not in disease controls. Further, IL-15 – known to drive TEM differentiation and proliferation – was also expressed in WG-granulomata. Thus, through acquisition of NK-like “innate” properties, IL-15 stimulated NKG2D+ TEM could interact with MIC+ cells within WG-granulomata, thereby sustaining inflammation and autoimmunity and promoting self-perpetuating pathology in WG.