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Long-term robustness of a T-cell system emerging from somatic rescue of a genetic block in T-cell development
- Source :
- EBioMedicine, EBioMedicine, Vol 59, Iss, Pp 102961-(2020)
- Publication Year :
- 2020
-
Abstract
- Backgound 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. Methods 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. Findings 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. Interpretation 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. Funding 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.
- Subjects :
- 0301 basic medicine
Male
Cell type
Research paper
Adolescent
Somatic cell
T cell
Reversion
T cells
lcsh:Medicine
Biology
T-cell development
X-Linked Combined Immunodeficiency Diseases
General Biochemistry, Genetics and Molecular Biology
Immunophenotyping
Clonal Evolution
03 medical and health sciences
0302 clinical medicine
T-Lymphocyte Subsets
medicine
Humans
Immunodeficiency
Genetic Testing
Progenitor cell
Child
Genetics
lcsh:R5-920
Severe combined immunodeficiency
Repertoire
Lymphopoiesis
TCR diversity
lcsh:R
Robustness (evolution)
Cell Differentiation
General Medicine
medicine.disease
Flow Cytometry
Killer Cells, Natural
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Case-Control Studies
Female
lcsh:Medicine (General)
Biomarkers
Subjects
Details
- ISSN :
- 23523964
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....f6e58bdf98aa38327632b86545e2b25b