Immunostimulation by induced expression of NKG2D and its MIC ligands in HTLV-1-associated neurologic disease
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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.
KeywordsNKG2D MIC ligands HTLV-1 Tax Transactivation
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.
- Azimi N, Jacobson S, Leist T, Waldmann TA (1999) Involvement of IL-15 in the pathogenesis of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL-2/15R beta receptor. J Immunol 163:4064–4072PubMedGoogle Scholar
- Lehky TJ, Fox CH, Koenig S, Levin MC, Flerlage N, Izumo S, Sato E, Raine CS, Osame M, Jacobson S (1995) Detection of human T lymphotropic virus type I (HTLV-1) Tax RNA in the central nervous system of HTLV-1 associated myelopathy/tropical spastic paraparesis by in situ hybridization. Ann Neurol 37:246–252CrossRefGoogle Scholar
- Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B (2004) Coordinated induction by IL-15 of a TCR-independent pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21:357–366PubMedCrossRefGoogle Scholar
- Parker CE, Nightingale S, Taylor GP, Weber J, Bangham CRM (1994) Circulating anti-Tax cytotoxic T lymphocytes from human T-cell leukemia virus type I-infected people, with and without tropical spastic paraparesis, recognizing multiple epitopes simultaneously. J Virol 68:2860–2868PubMedGoogle Scholar