Telomerase insufficiency in rheumatoid arthritis

Hiroshi Fujii, Lan Shao, Inés Colmegna, Jörg J. Goronzy, Cornelia M. Yand

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4360-4365
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number11
DOIs
Publication statusPublished - 2009 Mar 17
Externally publishedYes

Keywords

  • Apoptosis
  • Autoimmunity
  • Immunosenescence
  • Pathogenesis
  • Telomere

ASJC Scopus subject areas

  • General

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