Increased frequency of CD4+ and CD8+ follicular helper T cells in human lymph node biopsies during the earliest stages of rheumatoid arthritis

ObjectivesFollicular helper T cells (Tfh cells) provide key B cell help, and are essential in germinal center (GC) formation and (auto) antibody generation. To gain more insight into their role during the earliest phase of rheumatoid arthritis (RA) we analyzed their frequencies, phenotype and cytokine profile in peripheral blood and lymphoid tissues. MethodsUsing flow cytometry, we studied the frequency of Tfh and B cells in peripheral blood and lymph node (LN) needle biopsies. Three donor groups were included and compared: healthy controls (HCs), autoantibody positive individuals at risk for developing RA (RA-risk individuals), and early RA patients. Ex vivo stimulation of lymphocytes with PMA/ionomycin was performed to assess cytokine secretion by Tfh cells. ResultsIn blood, the frequency of circular Tfh cells (cTfh) did not differ between study groups. In lymphoid tissue, the frequency of Tfh cells correlated strongly with the frequency of CD19+ B cells. Compared to healthy controls, LN samples of RA patients and RA-risk individuals showed more CD19+ B cells and more CD4+CXCR5+ and CD8+CXCR5+ Tfh cells. These Tfh cells from LNs expressed less IL-21 upon ex vivo stimulation. ConclusionLN tissue of early RA patients as well as part of RA-risk individuals exhibit increased frequencies of Tfh cells correlating with increased numbers of B cells. Interestingly, IL-21 production is already aberrant in the very early at risk phase of the disease. This suggests that Tfh cells may present a novel rationale for therapeutic targeting during the preclinical stage of the disease to prevent further disease progression.