Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment

Karin M. E. Andersson, Nicola Filluelo Cavallini, Dan Hu, Mikael Brisslert, Ron Cialic, Hadi Valadi, Malin C. Erlandsson, Sofia Silfverswärd, Rille Pullerits, Vijay K. Kuchroo, Howard L. Weiner, Maria I. Bokarewa

T helper cells producing IL-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study we characterized specific pathogenic features of Th17 cells in RA.Using nano-string technology we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23, and IL-21, and transcriptional regulators RORγt and JAK2, they produced high levels of IL-23R, CCL20, GM-CSF and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios producing, Foxp3 and IL2RA deficient cells indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and LIF. We observed that anti-TNF treatment had limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), pro-inflammatory cytokines (IL-17F, IL-23, IL-21 and TNF) and adaptor molecules (CXCR5 and CTLA-4), essential for efficient trans-differentiation and accumulation of Th17 cells.This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may trans-differentiate from Tregs and contribute to perpetuation of the disease.