Characterization of MHC class I restricted cytotoxic T cell responses to tax in HTLV-1 infected patients with neurologic disease.

To understand the nature of the cytotoxic T cell response generated in human T lymphotropic virus type 1 (HTLV-1)-infected patients with HTLV-1-associated myelopathy/tropical spastic paraparesis, we cloned CTL from the peripheral blood and cerebrospinal fluid from patients with neurologic diseases and demonstrated the presence of HLA-A2, A3, and B14 restricted responses to the HTLV-1 p40x (tax) protein. We identified the minimal amino acid residues within the epitopes required for binding and recognition by HLA-A2- and B14-restricted CTL, identified the critical residues within the peptide sequence defining the HLA-A2-restricted response, and demonstrated that CTL can lyse T cells infected with HTLV-1. This study shows that the CTL response to HTLV-1 tax in patients with neurologic diseases is heterogenous in nature and is not confined to patients of a single HLA haplotype or to a specific region of the tax protein.

HTLV-I-specific cytotoxic T lymphocytes in the cerebrospinal fluid of patients with HTLV-I-associated neurological disease.

Recently, it has been shown that in patients with human T-cell lymphotropic virus type I (HTLV-I)-associated neurological disease, high levels of HTLV-I-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood. These CTLs predominantly recognized products of the pX region of HTLV-I, had a CD8+ phenotype, and were human leukocyte class I restricted. Moreover, these responses were not detected in asymptomatic, HTLV-I-seropositive individuals. This implied a role for these CTLs in the pathogenesis of the neurological disorder associated with HTLV-I. We have extended these observations by demonstrating HTLV-I-specific CTLs directly from lymphocytes obtained from the cerebrospinal fluid of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Uncultured cerebrospinal fluid lymphocytes were used directly as effectors on a variety of targets expressing HTLV-I. These cells were lysed in a virus-specific and HLA class I-restricted manner. Moreover, the cerebrospinal fluid lymphocytes were sorted into purified CD8+ populations, cloned by limiting dilution, and assayed for CTL activity. An exceedingly high proportion of these resultant lines were shown to be cytolytic and precursor frequency analysis indicated that as many as 1 in 500 cells were HTLV-I-specific CTLs. The majority of these CTL lines recognized HTLV-I gene products encoded within the pX region of HTLV-I. The significance of these HTLV-I-specific CTLs in the central nervous system of patients with HTLV-I-associated neurological disease is discussed with regard to the potential role of CTLs in the pathogenesis of this disease.