Telomerase insufficiency in rheumatoid arthritis.
In rheumatoid arthritis (RA), chronically stimulated T lymphocytes sustain tissue-destructive joint inflammation. Both naïve 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 naïve 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. Naïve 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 naïve 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.
Fujii
Hiroshi
H
Department of Medicine, Lowance Center for Human Immunology and Rheumatology, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Shao
Lan
L
Colmegna
Inés
I
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000209:etiology; D016022:Case-Control Studies; D016922:Cellular Senescence; D015536:Down-Regulation; D006412:Hematopoietic Stem Cells; D006801:Humans; D007156:Immunologic Memory; D013601:T-Lymphocytes / Q000473:pathology; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics; D016615:Telomere / Q000378:metabolism
C509186:TERT protein, human; D019098:Telomerase