Abstract
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.
Highlights
Human T-lymphotropic virus type I (HTLV-I) infects 20 million people worldwide [1]
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, the mechanism of this dysregulation remains to be defined
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, SLAM-associated protein (SAP), in CD8+ T cells distinguished HTLV-I infected individuals with and without neurologic disease
Summary
HTLV-I infects 20 million people worldwide [1]. While the majority of infected individuals are asymptomatic carriers (ACs) of the virus, 5–10% of infected people develop either adult T cell leukemia/lymphoma (ATL) [2] or a chronic, progressive neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [3,4]. HTLV-I-specific CTLs produce various factors including IFN-c and TNF-a that may suppress viral replication and kill infected cells or promote bystander activation and killing of nearby resident glial cells [7,8,9,10,11,12,13,14,15]. These studies suggested that HTLV-specific CTLs might be immunopathogenic in the inflammatory lesions of patients with HAM/TSP
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