Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease
Satoshi Nozuma, Yoshimi Enose-Akahata, Kory R. Johnson, Maria Chiara Monaco, Nyater Ngouth, Abdel Elkahloun, Joan Ohayon, Jun Zhu, Steven Jacobson
Satoshi Nozuma, Yoshimi Enose-Akahata, Kory R. Johnson, Maria Chiara Monaco, Nyater Ngouth, Abdel Elkahloun, Joan Ohayon, Jun Zhu, Steven Jacobson
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Research Article Immunology Infectious disease

Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease

Abstract

In this study, we examined and characterized disease-specific TCR signatures in cerebrospinal fluid (CSF) of patients with HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP). TCR β libraries using unique molecular identifier–based methodologies were sequenced in paired peripheral blood mononuclear cells (PBMCs) and CSF cells from HAM/TSP patients and normal healthy donors (NDs). The sequence analysis demonstrated that TCR β repertoires in CSF of HAM/TSP patients were highly expanded and contained both TCR clonotypes shared with PBMCs and uniquely enriched within the CSF. In addition, we analyzed TCR β repertoires of highly expanded and potentially immunopathologic HTLV-1 Tax11-19–specific CD8+ T cells from PBMCs of HLA-A*0201+ HAM/TSP and identified a conserved motif (PGLAG) in the CDR3 region. Importantly, TCR β clonotypes of expanded clones in HTLV-1 Tax11-19–specific CD8+ T cells were also expanded and enriched in the CSF of the same patient. These results suggest that exploring TCR repertoires of CSF and antigen-specific T cells may provide a TCR repertoire signature in virus-associated neurologic disorders.

Authors

Satoshi Nozuma, Yoshimi Enose-Akahata, Kory R. Johnson, Maria Chiara Monaco, Nyater Ngouth, Abdel Elkahloun, Joan Ohayon, Jun Zhu, Steven Jacobson

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Figure 1

TCR clonal expansion of TCR β repertoire in paired PBMCs and CSF of HAM/TSP patients and NDs.

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TCR clonal expansion of TCR β repertoire in paired PBMCs and CSF of HAM/...
(A) Representative analysis of T cell clonal expansion in PBMCs and CSF of a ND (ND-3) and a HAM/TSP patient (HAM-2). TCR β clonal expansion was analyzed by using the frequencies of clones ≥ 8 UMIs (colored wedges), clones with 2 ≤ UMIs < 8 (gray), and singletons (white). In the group of expanded clones, each wedge represents a unique clonotype with a defined CDR3 sequence, and the same clone shared by PBMCs and CSF in each individual is visualized in the same color. (B) Comparison of TCR clonal expansion by frequency of clones ≥ 8 UMIs between NDs (n = 5) and HAM/TSP patients (n = 9) in PBMCs and CSF using Mann-Whitney U test. Data represent mean ± SEM. (C) Correlation of TCR clonal expansion in PBMCs with frequencies of effector/memory and effector cells in PBMC CD4+ T cells (circles) and CD8+ T cells (squares) of NDs (opened shapes; n = 5) and HAM/TSP patients (closed shapes; n = 9) using Spearman’s rank correlation test. (D) Correlation of TCR clonal expansion in PBMCs with HTLV-1 PVL in PBMCs of HAM/TSP patients (n = 9) using Spearman’s rank correlation test.