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 cells in vivo which 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.

Keywords: HTLV-1-associated myelopathy/tropical spastic paraparesis; T cell receptor (TCR); TCR repertoire; adult T-cell leukemia/lymphoma; human T lymphotropic virus 1.

Figure 1

TCR-α and TCR-β chain gene structure. TCR-α and TCR-β chains consist of a variable (V) amino-terminal region and a constant (C) region. The complementarity-determining region 1 (CDR1) and CDR2 encoded in the TCR germline V genes, which are conserved across TCR-α and TCR-β. In contrast with CDR1 and CDR2, CDR3 is located at the junction between the rearranged V and joining (J) segments in TCR-α chain and V, diversity (D) and J segments in TCR-β chain. Additions of P- and N-nucleotides (P/N addition) are present in the junctions between the V, D, and J gene segments of the rearranged TCR-β chain and also between the V and J gene segments of all rearranged TCR-α chain.

Figure 2

Origin of TCR expanded clones in CSF of HAM/TSP patients. HAM/TSP patients had a higher clonal T cell expansion, especially CD8⁺ T cells (including HTLV-1-specific CTL), in PBMCs as well as in CSF. Within expanded T cell clones in CSF of HAM/TSP patients, most expanded CSF TCR-β clonotypes were derived from expanded T cell clones in PBMCs (yellow). A small but distinct fraction of these expanded TCR-β clonotypes were intrathecally enriched in CSF of HAM/TSP patients [reference (37)].