Stimulation of T Cell Autoreactivity by Anomalous Expression of NKG2D and Its MIC Ligands in Rheumatoid Arthritis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 16; pp. 9452 - 9457
• Main Authors: Groh, Veronika, Brühl, Anja, El-Gabalawy, Hani, Nelson, J. Lee, Spies, Thomas
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05-08-2003; National Acad Sciences
• Subjects: Arthritis; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - metabolism; Biological Sciences; CD28 Antigens - biosynthesis; CD4-Positive T-Lymphocytes - metabolism; Cell Division; Cell Line; Cell lines; Cultured cells; Cytokines; Cytokines - biosynthesis; Cytometry; Dose-Response Relationship, Drug; Down-Regulation; Fibroblasts - metabolism; Flow Cytometry; Humans; Immunohistochemistry; Immunology; Interleukin-15 - metabolism; Ligands; Major Histocompatibility Complex; Mica; Natural killer cells; Natural killer T cells; NK Cell Lectin-Like Receptor Subfamily K; Nucleic Acid Hybridization; Receptors; Receptors, Immunologic - biosynthesis; Receptors, Immunologic - chemistry; Receptors, Natural Killer Cell; RNA - metabolism; Signal Transduction; T cell receptors; T lymphocytes; T-Lymphocytes - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1632807100

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 α 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 α 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.