Increased Circulating Follicular Treg Cells Are Associated With Lower Levels of Autoantibodies in Patients With Rheumatoid Arthritis in Stable Remission

Abstract

Circulating Tfr cells are increased as patients with RA achieve stable remission of disease, and increased Tfr cells can suppress autoimmunity in RA patients to stabilize their condition. Our results provide novel insight into RA pathogenesis.

Control of Germinal Center Responses by T-Follicular Regulatory Cells

“…Interestingly due to their CD25 int nature CD45RA − cTfr find themselves in the fraction (FRIII) of blood Tregs that we previously identified as primarily Foxp3 int CD25 int non-Tregs (70). However, since we and others have confirmed that cTfr retain stable expression of Foxp3, a Treg-type demethylation signature, and suppressive function, it seems that FRIII may contain a mixture of Tregs and non-Tregs (26, 68, 71). This mixed nature of FRIII was recently confirmed by the finding that CD127 − CD25 int CD45RA − FRIII Tregs can be further divided into CD49d + CCR4 − , CCR4 − CD49d − , and CCR4 + CD49d − cells, with the CD49d fraction expressing inflammatory cytokines (72).…”

“…One group found that these cells were unable to suppress antibody production (68) while several groups found the opposite (26, 35, 71). Interestingly, Liu et al, found that cTfr suppressive activity increased in correlation with the sequential shift of cTfr from FRIII Foxp3 int into a highly-activated Foxp3 hi phenotype from healthy donors > active RA patients > patients in remission.…”

“…In the context of infection, cTfr expand during chronic viral and parasitic infections such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Schistosoma japonica (76–78) The increase of cTfr cell frequency in patients chronically infected with either HBV or HCV showed strong correlation with serum viral load in both infections. In rheumatoid arthritis, increased percentages of cTfr, decreased percentages of Tfh and a corresponding drop in the ratio of Tfh/Tfr was associated with stable disease and reduced levels of autoantibodies, while active disease was correlated to increased cTfr but no change in the Tfh/Tfr ratio (71). However, treatment may cause cTfr numbers to drop resulting in a high Tfh/Tfr ratio but no clear relationship between cTfr numbers and autoantibodies (79).…”

Follicular regulatory T cells: a novel target for immunotherapy?

“…Altered frequencies and/or the suppressive capacity of cTfr cells have been elucidated in a multitude of AIDs, including systemic AIDs and organ‐specific AIDs (shown in Table ). Systemic AIDs involve rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), ankylosing spondylitis (AS), IgG4‐related disease (IgG4‐RD) and common variable immune deficiency (CVID) . Organ‐specific AIDs involve multiple sclerosis (MS), myasthenia gravis (MG), Hashimoto's thyroiditis (HT), primary biliary cholangitis (PBC), type 1 diabetes (T1D) and ulcerative colitis (UC) .…”

“…The frequency of cTfr cells has negative or no correlation with disease activity, and the ratio of cTfr/cTfh is correlated with disease activity . Moreover, increased cTfr cells with enhanced suppressive function and activated CD45RA − Foxp3 high cTfr subset have been found in patients with RA in stable remission compared with patients with active RA and healthy controls . Percentages of cTfr and cTfh cells are decreased when prescribed with methotrexate …”