Altered Distribution of Circulating T Follicular Helper-Like Cell Subsets in Rheumatoid Arthritis Patients

Abstract

Objective: Recent studies on follicular regulatory T (Tfr) and follicular helper T (Tfh) cells suggest that they may participate in the pathogenesis of rheumatoid arthritis (RA). Here, we examine Tfr-like and Tfh-like cells and their subsets in RA and assess the correlations between these subsets with B cells and cytokines related to the pathogenesis of RA and their clinical significance.Methods: The study population consisted of 18 healthy controls and 47 RA patients (17 new onset, 57.00 ± 11.73 years; 30 treated RA patients, 57.56 ± 1.97 years). Disease activity scores in 28 joints were calculated. The positive rates of rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) were 82.9 and 89.4%, respectively. Cell subsets were analyzed using flow cytometry, and serum cytokine levels were measured using cytometric bead array.Results: Tfh-like and PD-1+ Tfh-like cells were elevated, and the distribution of Tfh-like cell subsets was altered with increased Tfh17-like and Tfh1/17-like cells in RA patients. The receiver operating characteristics curves for Tfh-like, Tfh17-like, Tfh1/17-like, and PD-1+ Tfh-like cells indicate improved RA diagnostic potential. RA patients had decreased regulatory T (Treg), Tfr-like, and memory Tfr-like (mTfr-like) cells and increased Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios. Tfh-like cells and their subsets, including Tfh1-like, Tfh2-like, Tfh1/17-like, and PD-1+ Tfh-like cells, were positively correlated with B cells. Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios were positively correlated with B cells in new-onset RA. Interleukin (IL)-2, IL-4, IL-17, interferon-γ, and tumor necrosis factor-α were positively correlated with Tfr-like and mTfr-like cells. IL-2 and IL-10 were positively correlated with Tfh-like and Tfh2-like cells. IL-4 was positively correlated with Tfh-like cells.Conclusions: Tfh-like and PD-1+ Tfh-like cells are increased, whereas Treg, Tfr-like, and mTfr-like cells are decreased in RA, leading to an imbalance in Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios. Tfh-like cells and a portion of their subsets as well as Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios are closely related to B cells. Dysfunction of cell subsets leads to abnormal levels of cytokines involved in the pathogenesis of RA. The altered distributions of Tfh-like cell subsets, especially Tfh1/17-like cells, represent potential therapeutic targets for treatment of RA.

Dynamics of circulating follicular helper T cell subsets and follicular regulatory T cells in rheumatoid arthritis patients according to HLA-DRB1 locus

“…In agreement with a wealth of data showing an expansion of circulating Tfh cells in RA patients ( 19 , 20 , 22 , 29 , 38 – 46 ), we report here an increased frequency of tTfh cells, defined as CD25 lo CD127 hi CXCR5 + CD45RA neg CD4 + CD3 + cells, in blood from RA patients, particularly those that present autoantibodies and are untreated. In addition, we detected a high frequency of CCR7 lo PD1 hi and IL-17 + IFNγ neg Tfh cell subsets in seropositive RA patients.…”

The Germinal Center Milieu in Rheumatoid Arthritis: The Immunological Drummer or Dancer?

“…Data from human studies on cTfh cells in RA patients clearly corroborate mouse data on aberrant Tfh numbers (Table 1). Several studies have reported an increase in cTfh cells in RA patients, accompanied by elevated IL-21 levels in some cases [65][66][67][68][69][70][71]. However, it is important to note that while there are increase Tfh numbers both in murine and human GCs, the underlying mechanism responsible for their expansion remains to be fully unraveled.…”

“…Arroyo-Villa et al [65] RA patients with active disease have a higher frequency of Tfh cells and a higher Tfh/Tfr ratio resulting from lower Tfr frequencies Zhang et al [66] Increased frequencies of Tfh cells and IL-21 in RA patients which correlates positively with DAS28 Wang et al [67], Zhou et al [69] Increased frequencies of Tfh cells in newly diagnosed RA patients correlating with activated B cells and DAS28 Niu et al [68] Elevated frequencies of Tfh cells, IL-21 and PD-1 in RA patients with active disease Nakayamada et al [70] Higher proportions of Tfh cells in RA patients with active disease and, treatment with Abatacept reduces Tfh cell levels. Su et al [71] Elevated frequencies of Tfh cells in RA patients compared to HCs…”

“…Su et al [71] Decreased frequencies of Tfr cells in RA patients compared to HCs Wang et al [72] Increased levels of Tfr cells in RA patients compared to HCs Macdonald et al [73] Elevated percentages of Tfr cells in RA patients Liu et al [74] Higher frequencies of Tfr and Tfr/Tfh cell ratio in RA patients with stable remission RA; Rheumatoid Arthritis, Tfh; T follicular helper cells, Tfr; T follicular regulatory cells, PD-1; Program cell death 1, DAS28; Disease activity score evaluated in 28 joints, HCs; healthy controls.…”

Increased Frequency of CD4+ Follicular Helper T and CD8+ Follicular T Cells in Human Lymph Node Biopsies during the Earliest Stages of Rheumatoid Arthritis

“…Studies into the role of T cells in the pathogenesis of RA in humans have mainly focused on the well-known Th1, Th2, Th17, and Treg subsets [ 21 , 22 , 23 ], during established disease, and in cell populations from peripheral blood and inflamed joints [ 22 , 24 ]. Studies of Tfh cells have focused on peripheral blood samples or inflamed tissue [ 4 , 25 , 26 , 27 ], while studies investigating Tfh cells in lymphoid organs during the earliest phases of autoimmunity are lacking. To the best of our knowledge, no study has analyzed CD8 + Tfh during the various stages of RA.…”