Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease

Abstract

The human T-lymphotropic virus type I (HTLV-I), the first human retrovirus to be characterized, is associated with adult T-cell leukaemia and a chronic progressive disease of the central nervous system termed tropical spastic paraparesis, or HTLV-I-associated myelopathy. Only 1% of individuals infected with HTLV-I develop clinical disease however. The various manifestations of an HTLV-I infection may be related to differences in the genetic backgrounds of individuals, infection with variant strains of HTLV-I, differences in viral tropism or host immune response to the virus. Whereas the humoral response to HTLV-I is well characterized, little is known about the human cellular immune response, such as the production of cytotoxic T lymphocytes. Here we report the presence of high levels of circulating HTLV-I-specific cytotoxic T lymphocytes in patients with HTLV-I associated neurological disease but not in HTLV-I seropositive individuals without neurological involvement. These cytotoxic T lymphocytes are CD8+, HLA class I- restricted and predominantly recognize the HTLV-I gene products encoded in the regulatory region pX. These findings suggest that HTLV-I-specific cytotoxic T lymphocytes may contribute to the pathogenesis of associated neurological disorders associated with HTLV-I.

Risk of human T‐lymphotropic virus type I‐associated diseases in Jamaica with common HLA types

“…The lack of a consistent association with more common HLA types suggests a fundamentally different pathogenesis for HAM/TSP, perhaps mediated in part by individual alleles that elicit strong CTL responses that cross-react with epitopes in the central nervous system. 2,6,7 In addition to our study's limited ability to investigate the role of individual alleles and haplotypes, our findings may not generalize to all of Jamaica because we could not include cases with rapidly lethal disease, particularly ATL. Nonetheless, the ATL cases were ascertained and recruited from the nation-wide lymphoma registry in Jamaica and therefore should be relatively representative of the population.…”

“…2,3 A unifying theory is that HLA alleles associated with HAM/ TSP, in contrast to alleles associated with ATL, elicit strong cytotoxic T-lymphocyte (CTL) responses against the Tax viral oncoprotein. 2,6,7 A complementary perspective is that greater HLA diversity conveys selective advantage against disease because the immune response is elicited by a greater variety of antigens, as described for human immunodeficiency virus (HIV) and AIDS. 8,9 With HIV, HLA class I heterozygotes progress more slowly to AIDS than do homozygotes.…”

Human T Cell Lymphotropic Virus Type I Tax Activates IL-15Rα Gene Expression Through an NF-κB Site

“…Patients with HAM/TSP also possess a high number of HTLV-I Tax-specific CD8 ϩ cells that might contribute to disease pathogenesis (41,53). IL-15 is important in the survival of CD8 ϩ memory cells (54); therefore, it is possible that IL-15 released from HTLV-I-infected cells acts in a paracrine fashion on neighboring CD8 ϩ HTLV-I-specific cells.…”

Genetic control and dynamics of the cellular immune response to the human T–cell leukaemia virus, HTLV–I

“…It is of central importance in the virus dynamics because, as well as transactivating viral transcription, it drives host cell proliferation by transactivating a large number of host genes, notably IL-2 and IL-2 receptor. Finally, Tax is the dominant target antigen recognized by HTLV-I-speci¢c cytotoxic T lymphocytes in most responding individuals (Jacobson et al 1990;Kannagi et al 1992;Parker et al 1992Parker et al , 1994. Thus the Tax protein is at the centre of both e¤cient HTLV-I replication and the host attack on the virus.…”