Immunostimulation by induced expression of NKG2D and its MIC ligands in HTLV-1-associated neurologic disease.
The NKG2D receptor costimulates effector/memory CD8 T cells and is normally absent on CD4 T cells but can be induced by T cell antigen receptor complex stimulation and interleukin-15 (IL-15). Among its ligands are the human major histocompatibility complex class I-related MICA and MICB, which have a restricted tissue distribution but are frequently associated with malignancies and some microbial infections. Moreover, aberrant expression of MIC may promote autoimmune disease progression. Human T cell lymphotropic virus type I (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the central nervous system that resembles multiple sclerosis. Disease progression involves production of IL-15 and its receptor through transactivation by the viral Tax regulator protein, an activated immune response state, and local cytokine production and T cell fratricide by Tax-specific cytotoxic T lymphocytes (CTL). This study shows that as with CD8 T cells, substantial proportions of HAM/TSP patient CD4 T cells are positive for NKG2D and that large numbers of T cells from both subsets express MIC, which can be transactivated by Tax independent of nuclear factor kappaB. Engagement of MIC by NKG2D promotes spontaneous HAM/TSP T cell proliferation and, apparently, CTL activities against HTLV-1-infected T cells. These results reveal a viral strategy that may exploit immune stimulatory mechanisms to negotiate a balance between promotion and limitation of infected host T cell expansions.
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA.
Nazli
N
Azimi
Steven
S
Jacobson
Yuetsu
Y
Tanaka
Lawrence
L
Corey
Veronika
V
Groh
Thomas
T
Spies
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007114:Immunization; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000502:physiology; D015493:Paraparesis, Tropical Spastic / Q000097:blood / Q000276:immunology* / Q000821:virology; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D015533:Transcriptional Activation
D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C120635:TAX1BP1 protein, human