Expansion of circulating NKG2D+ effector memory T-cells and expression of NKG2D-ligand MIC in granulomaous lesions in Wegener's granulomatosis

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