Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis

Abstract

Effector T cell responses can be modulated by competing positive or negative signals transduced by natural killer (NK) cell receptors. This raises the possibility that dominant T cell stimulation might promote autoimmune reactions. In rheumatoid arthritis (RA), the severity of autoimmune and inflammatory joint disease correlates with large numbers of CD4 ؉ CD28 ؊ T cells, which are scarce in healthy individuals. For poorly defined reasons, these T cells are autoreactive, implying that they may contribute to disease manifestations. CD4 ؉ CD28 ؊ T cells in peripheral blood and synovial tissue of RA patients were found to express NKG2D, a costimulatory receptor that is absent on normal CD4 T cells. NKG2D was induced by tumor necrosis factor ␣ and IL-15, which are abundant in inflamed synovia and RA patient sera. RA synoviocytes aberrantly expressed the stress-inducible MIC ligands of NKG2D, which stimulated autologous CD4 ؉ CD28 ؊ T cell cytokine and proliferative responses. Peripheral blood serum samples of RA patients contained substantial amounts of synoviocyte-derived soluble MICA, which failed to induce down-modulation of NKG2D because of the opposing activity of tumor necrosis factor ␣ and IL-15. These results suggest that a profound dysregulation of NKG2D and its MIC ligands may cause autoreactive T cell stimulation, thus promoting the self-perpetuating pathology in RA and possibly other autoimmune diseases.

Loss of nonclassical MHC molecules MIC-A/B expression during progression of uveal melanoma

“…The mAb used for MIC-A/B (6D4) and NKG2D (5C6) were kindly provided by Veronica Groh and Thomas Spies, Fred Hutchinson Cancer Research Center, Seattle, USA and its characteristics have been described Groh et al, 1999Groh et al, , 2003Steinle et al, 2001).…”

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

“…Recent work has shown that various cellular stresses such as reactive oxygen species and DNA damage up-regulate MICA/B expression (Peraldi et al, 2009) and that dysregulated 5 expression of NKG2D ligands is involved in the development of inflammatory and autoimmune diseases such as rheumatoid arthritis, celiac disease and type 1 diabetes (Groh et al, 2003;Meresse et al, 2004;Ogasawara et al, 2004).…”

Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus

“…Human NKG2D was originally identified on NK cells, TCRcd + cells and TCRab + CD8 + T lymphocytes, but CD4 + NKG2D + T cells have been described in rheumatoid arthritis (RA) and some cancer patients [31,32]. Goronzy and Weyand [33] hypothesized that CD4 + T lymphocytes expressing NKG2D and aNKR represent senescent effector-memory T cells that may contribute to the pathogenesis of RA and other chronic inflammatory disorders [15].…”

“…Goronzy and Weyand [33] hypothesized that CD4 + T lymphocytes expressing NKG2D and aNKR represent senescent effector-memory T cells that may contribute to the pathogenesis of RA and other chronic inflammatory disorders [15]. NKG2D might exacerbate RA progression by reacting with its ligands abnormally expressed by the inflamed synovium [31,33]. On the other hand, stimulation by soluble MIC molecules (sMIC) has been proposed to account for the increased frequencies of CD4 + NKG2D + T cells producing Fas ligand in patients bearing MIC + tumours [32].…”