Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis.
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 alpha 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 alpha 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.
Groh
Veronika
V
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA 98109, USA.
Bruhl
Anja
A
El-Gabalawy
Hani
H
Nelson
J Lee
JL
Spies
Thomas
T
D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000378:metabolism; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000378:metabolism; D008024:Ligands; D008285:Major Histocompatibility Complex; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009693:Nucleic Acid Hybridization; D012313:RNA / Q000378:metabolism; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000737:chemistry; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018106:CD28 Antigens; D016207:Cytokines; D019409:Interleukin-15; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D014409:Tumor Necrosis Factor-alpha; D012313:RNA