期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 11, 页码 4360-4365出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0811332106
关键词
telomere; immunosenescence; pathogenesis; autoimmunity; apoptosis
资金
- National Institutes of Health [RO1 AR42527, RO1 AR41974, RO1 AI44142, RO1 AI57266, RO1 EY11916, RO1 AG15043]
- Diane Wolf Discovery Fund
In rheumatoid arthritis (RA), chronically stimulated T lymphocytes sustain tissue-destructive joint inflammation. Both naive and memory T cells in RA are prematurely aged with accelerated loss of telomeres suggesting excessive proliferative pressure or inadequate telomeric maintenance. Upon stimulation, RA naive CD4 T cells are defective in up-regulating telomerase activity (P < 0.0001) due to insufficient induction of the telomerase component human telomerase reverse transcriptase (hTERT); T cell activation and cell cycle progression are intact. Telomerase insufficiency does not affect memory T cells or CD34 hematopoietic stem cells and is present in untreated patients and independent from disease activity. Knockdown of hTERT in primary human T cells increases apoptotic propensity (P = 0.00005) and limits clonal burst (P = 0.0001) revealing a direct involvement of telomerase in T cell fate decisions. Naive RA CD4 T cells stimulated through the T cell receptor are highly susceptible to apoptosis, expanding to smaller clonal size. Overexpression of ectopic hTERT in naive RA T cells conveys apoptotic resistance (P = 0.008) and restores proliferative expansion (P < 0.0001). Telomerase insufficiency in RA results in excessive T cell loss, undermining homeostatic control of the naive T cell compartment and setting the stage for lymphopenia-induced T cell repertoire remodeling. Restoring defective telomerase activity emerges as a therapeutic target in resetting immune abnormalities in RA.
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