Increased Frequency of HTLV-1 Tax Specific CD8+ Regulatory T-Cells in HTLV-1 Infected Individuals.

Abstract

Abstract 3676Poster Board III-612Regulatory T-cells (Tregs) mediate self-tolerance and moderate the immune response to various antigens. Their frequency and suppressive function are reduced in various autoimmune diseases like type 1 diabetes mellitus, systemic lupus, and rheumatoid arthritis, but may be excessive in certain malignancies. The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus with myriad clinical manifestations, most notably adult T-cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP). We have previously described the decreased frequency and function of HTLV-1 specific CD8+ T-cells in ATLL patients compared to asymptomatic carriers (ACs) and healthy controls (HCs). We have also reported the relative exhaustion of HTLV-1 specific cytotoxic T-lymphocytes (CTLs) compared to cytomegalovirus (CMV)-specific CTLs in ACs, as demonstrated by upregulation of the co-inhibitory molecule, programmed death 1 (PD-1). Recent evidence supports the existence of CD8+ Tregs in humans, defined primarily by forkhead box P3 (FOXP3) transcription factor expression. Although a classic Treg phenotypic marker, FOXP3's aberrant expression makes it a less reliable marker in the setting of ATLL. Low expression or absence of interleukin 7 receptor (IL-7R) (CD127lo/-) on CD25+ T-cells has provided a useful alternative Treg phenotype, allowing preservation of cell viability for functional assays. Existing studies have focused mostly on CD4+ Tregs and a few on CD8+ Tregs in malignancy, but little is known about their involvement in the persistence of chronic viral infections like HTLV-1. In chronic HTLV-1 infection, FOXP3+CD25+ and CD127lo/-CD25+ Tregs comprise 8.3±4.6% and 8.1±4.3% of overall CD8+ T-cells, respectively (n=14). Expression of the FOXP3+CD25+ phenotype in CD8+ T-cells had a tendency towards correlation with the CD127lo/-CD25+ phenotype (r=0.561, p=0.073, n=11). Among ACs, we observed the CD127lo/-CD25+ Treg phenotype in HTLV-1 Tax-specific CD8+ T-cells (45±16.5%, n=8), which was significantly greater than CMV-specific CD8+ Tregs (25±15.8%, n=6) (p<0.05, Figure 1), as characterized by phycoerythrin-labelled HLA-A*2402 Tax301-309 or HLA-A*0201 Tax11-19 and HLA-A*24/ HLA-A*02 CMV tetramers respectively. We have demonstrated that the CD8+CD127lo/-CD25+ phenotype could be an alternative marker of CD8+ Tregs. These observations suggest that HTLV-1 specific CD8+ Tregs could be implicated in the impaired clearance of HTLV-1 infected and transformed cells. This surrogate marker may facilitate further exploration of the immunological significance of antigen specific CD8+ Tregs in chronic viral infection. [Display omitted] Disclosures:No relevant conflicts of interest to declare.