In HAM/TSP patients, there are reports on complementarity determining region 3 (CDR3) TCR repertoire analysis in which no significant differences of expanded T-cell clones in HAM/TSP patients were observed when compared to asymptomatic carriers 14. Moreover, there was a higher clonal expansion in both peripheral blood and CSF compartments of MS patients compared to controls 13. Previously, we have reported that the TCR clonal repertoire in the peripheral blood of MS patients was different than what is observed from the T-cell profile within the CSF. With improved TCR-sequencing technological development, efforts in identifying immune T-cell signatures in blood, CSF and brain lesions of MS patients have been initiated, with the goal to better characterize MS disease processes 11 and to distinguishing subsets of MS patients 12.

A comprehensive characterization of the T-cell receptor repertoire (TCR) in MS patients would therefore be of value to determine if a ‘signature’ of TCRs can be identified, particularly in comparison with a clinically similar disease like HAM/TSP in which immunopathogenic T cells triggered by a known virus have been thought to play a role in disease pathogenesis 10. It is therefore been hypothesized that in MS, environmental triggers (including viruses) in genetically susceptible individuals lead to immunopathogenic T cell responses that contribute to the development of disease 8, 9. However, unlike HTLV-I mediated HAM/TSP, the antigen(s) driving the inflammatory autoimmune-mediated response in MS patients are still unknown although viruses have long been considered potential environmental ‘triggers’ in this disorder 7. Indeed, the primary progressive form of MS is clinically similar to HAM/TSP 6 and even, to this day, many patients with HAM/TSP are misdiagnosed as MS. Similarly, trafficking of T-cells from the peripheral blood into the CNS is also a hallmark of a more common inflammatory, demyelinating disease, multiple sclerosis (MS) 5. In HAM/TSP, circulating HTLV-I antigen-specific T-cells have been shown to cross the blood-brain barrier, infiltrate the spinal cord and are thought to initiate an immunopathogenic response against virus and/or components of the CNS 4. While most remain asymptomatic, a small proportion develop clinical disease including adult T cell lymphoma (ATL), HAM/TSP and other autoimmune inflammatory disorders 3. Approximately 20–30 million people are infected worldwide. It is a chronic inflammatory immune-mediated disease of the central nervous system (CNS), associated with increased HTLV-I proviral loads (PVL) in blood and cerebrospinal fluid (CSF) 2. Human T-cell lymphotropic virus type I (HTLV-I) is the causative agent in a progressive neurologic disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) 1.

This suggests that a TCR-repertoire signature may be identified in a subset of patients with MS. While no clones that shared the same CDR3 amino acid sequences were seen in either HC or MS patients, there was a cluster of related CDR3 amino acid sequences observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. Only non-shared or “private” TCR repertoires was observed. Despite higher TCR clonal expansions in HAM/TSP patients, no disease-specific TCRs were shared among patients. Surprisingly, MS patients showed a higher diversity of TCR repertoires than other groups. In addition, longitudinal analysis of TCR repertoires from HAM/TSP patients demonstrated a correlation of the TCR clonal expansion with HTLV-I proviral load.

While HAM/TSP patients showed a higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subjects. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). In this study, we applied an unbiased molecular technique – unique molecular identifier (UMI) library-based strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. We hypothesized that a T-cell receptor (TCR) clonal repertoire ‘signature’ could distinguish HAM/TSP patients from healthy controls, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease such as MS. In this study we characterized the TCR repertoire profiles in patients with chronic progressive inflammatory neurological disorders including HAM/TSP, associated with human T-cell lymphotropic virus type I (HTLV-I) infection, and multiple sclerosis (MS), an inflammatory, demyelinating disease of the CNS of unknown etiology.

Lossius a immune repertoire