Impaired function of human T-lymphotropic virus type 1 (HTLV-1)–specific CD8+ T cells in HTLV-1–associated neurologic disease

Abstract

Abstract Despite abundant activated virus-specific cytotoxic T lymphocytes (CTLs), patients with human T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) showed a significantly higher frequency of infected T cells than did healthy virus carriers (HVCs). Here, we demonstrate that at a given proviral load, the frequency of CD8+ T cells that are negative for specific costimulatory molecules was significantly higher in HAM/TSP than in age-matched HVCs and uninfected healthy controls (HCs), whereas the frequency of intracellular perforin-positive CD8+ T cells was significantly lower in both HAM/TSP and HVCs than in HCs. An inverse correlation between HTLV-1 proviral load (PVL) and percent perforin-positive CD8+ T cells were observed only in disease-protective allele HLA-A*02–positive HVCs, but not in HAM/TSP patients, whether HLA-A*02 positive or negative, nor in HLA-A*02–negative HVCs. Significantly lower perforin expression was observed in HTLV-1–specific than in cytomegalovirus-specific CD8+ T cells. Majority of HTLV-1–specific CD8+ T cells in HVCs showed a CD28−CD27+ phenotype, whereas HAM/TSP showed a CD28−CD27− phenotype. HTLV-1–specific CD8+ T cells from HAM/TSP patients showed significantly lower degranulation than HVCs by CD107a mobilization assay. These findings suggest that an impaired function of HTLV-1–specific CTLs is associated with failing antiviral control and disease HAM/TSP.