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Human natural killer (NK)-cell receptors are expressed by NK cells and some T cells, primarily TCR+CD8+ cytotoxic T lymphocytes (CTLs). Inhibitory NK cell receptors (iNKRs) can down-regulate antigen-mediated T-cell effector functions, including cytotoxic activity and cytokine release. In the present study we demonstrate that CD3+ T cells that bind tetramers of HLA-E and express its ligand, the NK-cell inhibitory receptor CD94/NKG2A, were significantly decreased in frequency in patients with human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) but not in asymptomatic HTLV-1 carriers. These cells were either alphabeta or gammadelta T cells. T-cell receptor (TCR) Vbeta-specific reverse transcription-polymerase chain reaction and spectratyping analysis revealed that the TCR repertoire in directly isolated HLA-E tetramer-positive cells from peripheral blood mononuclear cells was skewed in both HTLV-1-infected and healthy individuals. However, oligoclonally or monoclonally expanded levels of TCR Vbetawere more frequently detected within HTLV-1-infected individuals than healthy controls. Importantly, HLA-E tetramer-positive or NKG2A+ T cells from HTLV-1 patients do not express Tax and display different TCR usage from the immunodominant Tax11-19-specific CD8+ T cells, suggesting that they do not encounter HTLV-1-infected cells. The expression of NK cell-associated receptors by clonally expanded CD8+ T cells during chronic viral infection suggests that these receptors play a role in regulating CD8+ T cell-mediated antiviral immune responses and that a decrease of this cell subset results in an increased risk of inflammatory diseases such as HAM/TSP.