HTLV-I-specific CD8 + T cells have been characterized with high frequencies in peripheral blood and cerebrospinal fluid and production of proinflammatory cytokines, which contribute to central nervous system inflammation in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, little is known about the differences in CD8 + T cell activation status between asymptomatic carrier (ACs) and patients with HAM/TSP. The expression of CD244, a signaling lymphocyte activation molecule (SLAM) family receptor, was significantly higher on CD8 + T cells in HTLV-I-infected patients, both ACs and patients with HAM/TSP, than those on healthy normal donors (NDs). Blockade of CD244 inhibited degranulation and IFN-γ production in CD8 + T cells of patients with HAM/TSP, suggesting that CD244 is associated with effector functions of CD8 + T cells in patients with HAM/TSP. Moreover, SLAM-associated protein (SAP) was overexpressed in patients with HAM/TSP compared to ACs and NDs. SAP expression in Tax-specific CTLs was correlated in the HTLV-I proviral DNA loads and the frequency of the cells in HTLV-I-infected patients. SAP knockdown by siRNA also inhibited IFN-γ production in CD8 + T cells of patients with HAM/TSP. Thus, the CD244/SAP pathway was involved in the active regulation of CD8 + T cells of patients with HAM/TSP, and may play roles in promoting inflammatory neurological disease.
Human T-lymphotropic virus type I (HTLV-I) is a retrovirus that persistently infects 20 million people worldwide. The majority of infected individuals are asymptomatic carriers of the virus, but 5–10% of infected people develop either adult T cell leukemia/lymphoma (ATL) or a chronic, progressive neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is characterized by central nervous system (CNS) inflammation including HTLV-I-specific CD8 + T cells where disease progression and pathogenesis is associated with a dysregulation of antigen-specific CD8 + T cells, although the mechanism of this dysregulation remains to be defined. Here we demonstrate that a signaling lymphocyte activation molecule (SLAM) family of receptors, CD244, was overexpressed on CD8 + T cells of HTLV-I-infected patients than those of healthy normal donors, and that the upregulation of the adaptor protein, SAP, in CD8 + T cells distinguished HTLV-I infected individuals with and without neurologic disease. Both CD244 and SAP were associated with effector functions (high expression of IFN-γ) of CD8 + T cells in patients with HAM/TSP. This finding has important implication for T cell-mediated pathogenesis in human chronic viral infection associated with imbalance of immune function.