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Immunostimulation by induced expression of NKG2D and its MIC ligands in HTLV-1-associated neurologic disease

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Abstract

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 κB. 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.

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Acknowledgements

This work was supported by National Institutes of Health grants AI042528 (L.C.) and AI30581 and AI52319 (T.S.). All experiments comply with current laws of the USA.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA, 98109, USA

    Nazli Azimi, Lawrence Corey, Veronika Groh & Thomas Spies

  2. Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA

    Steven Jacobson

  3. Department of Infectious Disease and Immunology, Faculty of Medicine, Okinawa-Asia Research Center of Medical Science, University of the Ryukyus, Nishihara, Okinawa, 903-0215, Japan

    Yuetsu Tanaka

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  1. Nazli Azimi
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  2. Steven Jacobson
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  3. Yuetsu Tanaka
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  4. Lawrence Corey
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  5. Veronika Groh
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  6. Thomas Spies
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Correspondence to Thomas Spies.

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Azimi, N., Jacobson, S., Tanaka, Y. et al. Immunostimulation by induced expression of NKG2D and its MIC ligands in HTLV-1-associated neurologic disease. Immunogenetics 58, 252–258 (2006). https://doi.org/10.1007/s00251-006-0082-9

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  • DOI: https://doi.org/10.1007/s00251-006-0082-9

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