Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus.
The NKG2D receptor stimulates natural killer cell and T cell responses upon engagement of ligands associated with malignancies and certain autoimmune diseases. However, conditions of persistent NKG2D ligand expression can lead to immunosuppression. In cancer patients, tumor expression and shedding of the MHC class I-related chain A (MICA) ligand of NKG2D drives proliferative expansions of NKG2D(+)CD4(+) T cells that produce interleukin-10 (IL-10) and transforming growth factor-beta, as well as Fas ligand, which inhibits bystander T cell proliferation in vitro. Here, we show that increased frequencies of functionally equivalent NKG2D(+)CD4(+) T cells are inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE), suggesting that these T cells may have regulatory effects. The NKG2D(+)CD4(+) T cells correspond to a normally occurring small CD4 T cell subset that is autoreactive, primed to produce IL-10, and clearly distinct from proinflammatory and cytolytic CD4 T cells with cytokine-induced NKG2D expression that occur in rheumatoid arthritis and Crohn's disease. As classical regulatory T cell functions are typically impaired in SLE, it may be clinically significant that the immunosuppressive NKG2D(+)CD4(+) T cells appear functionally uncompromised in this disease.
Dai
Zhenpeng
Z
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Turtle
Cameron J
CJ
Booth
Garrett C
GC
Riddell
Stanley R
SR
Gooley
Theodore A
TA
Stevens
Anne M
AM
Spies
Thomas
T
Groh
Veronika
V
D017668:Age of Onset; D015703:Antigens, CD / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005312:Fetal Blood / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000627:therapeutic use*; D012016:Reference Values; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology
D015703:Antigens, CD; D015704:CD4 Antigens; D016207:Cytokines; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016212:Transforming Growth Factor beta; D016753:Interleukin-10