Details

Autor(en) / Beteiligte

• Kury, Patrick
• Führer, Marita
• Fuchs, Sebastian
• Lorenz, Myriam R.
• Giorgetti, Orlando Bruno
• Bakhtiar, Shahrzad
• Frei, Andreas P.
• Fisch, Paul
• Boehm, Thomas
• Schwarz, Klaus
• Speckmann, Carsten
• Ehl, Stephan

Titel

Long-term robustness of a T-cell system emerging from somatic rescue of a genetic block in T-cell development

Ist Teil von

• EBioMedicine, 2020-09, Vol.59, p.102961-102961, Article 102961

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2020

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• The potential of a single progenitor cell to establish and maintain long-term protective T-cell immunity in humans is unknown. For genetic disorders disabling T-cell immunity, somatic reversion was shown to support limited T-cell development attenuating the clinical phenotype. However, the cases reported so far deteriorated over time leaving unanswered the important question of long-term activity of revertant precursors and the robustness of the resulting T-cell system. We applied TCRβ-CDR3 sequencing and mass cytometry on serial samples of a now 18 year-old SCIDX1 patient with somatic reversion to analyse the longitudinal diversification and stability of a T-cell system emerging from somatic gene rescue. We detected close to 105 individual CDR3β sequences in the patient. Blood samples of equal size contained about 10-fold fewer unique CDR3β sequences compared to healthy donors, indicating a surprisingly broad repertoire. Despite dramatic expansions and contractions of individual clonotypes representing up to 30% of the repertoire, stable diversity indices revealed that these transient clonal distortions did not cause long-term repertoire imbalance. Phenotypically, the T-cell system did not show evidence for progressive exhaustion. Combined with immunoglobulin substitution, the limited T-cell system in this patient supported an unremarkable clinical course over 18 years. Genetic correction in the appropriate cell type, in our patient most likely in a T-cell biased self-renewing hematopoietic progenitor, can yield a diverse T-cell system that provides long-term repertoire stability, does not show evidence for progressive exhaustion and is capable of providing protective and regulated T-cell immunity for at least two decades. DFG EH 145/9-1, DFG SCHW 432/4-1 and the German Research Foundation under Germany's Excellence Strategy–EXC-2189–Project ID: 390939984.