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 4

TCR clonal expansion of TCR β repertoire in PBMCs, enriched CD8+ T cells, and sorted Tax11-19–specific CD8+ T cells of HAM/TSP patients with HLA-A*0201.

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TCR clonal expansion of TCR β repertoire in PBMCs, enriched CD8+ T cells...
(A) Tax tetramer staining in CD3+ T cells of PBMCs (left), enriched CD8+ T cells (center), and sorted Tax11-19–specific CD8+ T cells (right) in a HAM/TSP patient (HAM-11). (B) Representative pie charts of T cell clonal expansion in PBMCs, enriched CD8+ T cells, and sorted Tax11-19–specific CD8+ T cells of a HAM/TSP patient (HAM-11). TCR β clonal expansion was analyzed by using the frequency 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 among PBMCs, CD8+ T cells, and Tax11-19–specific CD8+ T cells is visualized in the same color. (C) Comparison of TCR clonal expansion by frequency of clones ≥ 8 UMIs among PBMCs, enriched CD8+ T cells, and sorted Tax11-19–specific CD8+ T cells in HAM/TSP patients with HLA-A*0201 (n = 7) using the Friedman test’s post hoc test. Data represent mean ± SEM. (D) Comparison of Shannon diversity among PBMCs, enriched CD8+ T cells, and sorted Tax11-19–specific CD8+ T cells in HAM/TSP patients (n = 7) using the Friedman test’s post hoc test. Data represent mean ± SEM.