ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis

Karnail Singh, Pratima Deshpande, Sergey Pryshchep, Inés Colmegna, Vladimir Liarski, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Immune responses to citrullinated neoantigens and clinical efficacy of costimulation blockade indicate a general defect in maintaining T cell tolerance in rheumatoid arthritis (RA). To examine whether TCR threshold calibration contributes to disease pathogenesis, signaling in RA T cells was quantified. RA patients had a selective increase in ERK phosphorylation compared with demographically matched controls due to a mechanism distal of Ras activation. Increased ERK responses included naive and memory CD4 and CD8 T cells and did not correlate with disease activity. The augmented ERK activity delayed SHP-1 recruitment to the TCR synapse and sustained TCR-induced Zap70 and NF-κB signaling, facilitating responses to suboptimal stimulation. Increased responsiveness of the ERK pathway was also a characteristic finding in the SKG mouse model of RA where it preceded clinical symptoms. Treatment with subtherapeutic doses of a MEK-1/2 inhibitor delayed arthritis onset and reduced severity, suggesting that increased ERK phosphorylation predisposes for autoimmunity and can be targeted to prevent disease.

Original languageEnglish (US)
Pages (from-to)8258-8267
Number of pages10
JournalJournal of Immunology
Volume183
Issue number12
DOIs
StatePublished - Dec 15 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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