ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis.
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-kappaB 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.
Singh
Karnail
K
Department of Medicine, Kathleen B and Mason I Lowance Center for Human Immunology and Rheumatology, Emory UniversitySchool of Medicine, Atlanta, GA 30322, USA.
Deshpande
Pratima
P
Pryshchep
Sergey
S
Colmegna
Inés
I
Liarski
Vladimir
V
Weyand
Cornelia M
CM
Goronzy
Jörg J
JJ
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002138:Calibration / Q000592:standards; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010766:Phosphorylation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D011948:Receptors, Antigen, T-Cell; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases