T cell receptor repertoire analysis in HTLV-1-associated diseases

Abstract

Human T lymphotropic virus 1 (HTLV-1) is a human retrovirus identified as the causative agent in adult T-cell leukemia/lymphoma (ATL) and chronic-progressive neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 is estimated to infect between 5-20 million people worldwide, although most infected individuals remain asymptomatic. HTLV-1 infected persons carry an estimated lifetime risk of approximately 5% of developing ATL, and between 0.25% and 1.8% of developing HAM/TSP. Most HTLV-1 infection is detected in CD4+T cellsin vivowhich causes the aggressive malignancy in ATL. In HAM/TSP, the increase of HTLV-1 provirus induces immune dysregulation to alter inflammatory milieu, such as expansion of HTLV-1-specific CD8+T cells, in the central nervous system of the infected subjects, which have been suggested to underlie the pathogenesis of HAM/TSP. Factors contributing to the conversion from asymptomatic carrier to disease state remain poorly understood. As such, the identification and tracking of HTLV-1-specific T cell biomarkers that may be used to monitor the progression from primary infection to immune dysfunction and disease are of great interest. T cell receptor (TCR) repertoires have been extensively investigated as a mechanism of monitoring adaptive T cell immune response to viruses and tumors. Breakthrough technologies such as single-cell RNA sequencing have increased the specificity with which T cell clones may be characterized and continue to improve our understanding of TCR signatures in viral infection, cancer, and associated treatments. In HTLV-1-associated disease, sequencing of TCR repertoires has been used to reveal repertoire patterns, diversity, and clonal expansions of HTLV-1-specific T cells capable of immune evasion and dysregulation in ATL as well as in HAM/TSP. Conserved sequence analysis has further been used to identify CDR3 motif sequences and exploit disease- or patient-specificity and commonality in HTLV-1-associated disease. In this article we review current research on TCR repertoires and HTLV-1-specific clonotypes in HTLV-1-associated diseases ATL and HAM/TSP and discuss the implications of TCR clonal expansions on HTLV-1-associated disease course and treatments.

Diversity of HLA-A2-Restricted and Immunodominant Epitope Repertoire of Human T-Lymphotropic Virus Type 1 (HTLV-1) Tax Protein: Novel Insights among N-Terminal, Central and C-Terminal Regions

“…Tax 11–19 (LLFGYPVYV) epitope present in the N-terminal region of the protein has been associated with the induction of cytotoxic CD8 + T cells that respond by producing high levels of IFN-γ, which is more prominent in HAM/TSP patients [ 17 ]. On the other hand, the C-terminal end of Tax is associated with the development of Tax 301–309 -specific cytotoxic CD8 + T-cell responses, which were recently linked with protection against challenge with MT-2 cell lines using a humanized mouse model [ 18 , 19 ].…”

“…In this scenario, the development of immunotherapeutic or vaccine strategies becomes crucial for controlling the diseases associated with the virus. Considering the persistence of this retrovirus and that a humoral immune response would be insufficient for controlling the proviral load, vaccines harnessing the proinflammatory response of cytotoxic T lymphocytes (CTLs) induced by Tax could contribute as therapeutic strategies [ 19 , 20 , 21 , 22 ].…”