Altered Circulating Follicular T Helper Cell Subsets and Follicular T Regulatory Cells Are Indicators of a Derailed B Cell Response in Lupus, Which Could Be Modified by Targeting IL-21R

Abstract

Systemic lupus erythematosus (SLE) is characterized by the breakdown of self-tolerance, the production of high-affinity pathogenic autoantibodies and derailed B cell responses, which indicates the importance of central players, such as follicular T helper (TFH) subsets and follicular T regulatory (TFR) cells, in the pathomechanism of the disease. In this study, we aimed to analyze the distribution of the circulating counterparts of these cells and their association with disease characteristics and B cell disproportions in SLE. We found that the increased percentage of activated circulating TFH (cTFH) and cTFR cells was more pronounced in cutaneous lupus; however, among cTFH subsets, the frequency of cTFH17 cells was decreased in patients with lupus nephritis. Furthermore, the decreased proportion of cTFH17 cells was associated with low complement C4 levels and high disease activity scores. We also investigated whether the blocking of the IL-21 receptor (IL-21R) with an anti-IL-21R monoclonal antibody inhibits the B cell response, since IL-21 primarily produced by TFH cells potentially promotes humoral immunity. We observed that anti-IL-21R inhibited plasmablast generation and immunoglobulin production. Our study demonstrated that, besides cTFR/cTFH imbalance, cTFH17 cells play a crucial role in SLE pathogenesis, and modulating cTFH-B cell interaction through the IL-21/IL-21R pathway may be a promising therapeutic strategy to suppress the pathological B cell response.

BAFFR expression in circulating T follicular helper (CD4+CXCR5+PD-1+) and T peripheral helper (CD4+CXCR5−PD-1+) cells in systemic lupus erythematosus

“…Previous studies have reported an increased frequency of cTfh cells in several autoimmune diseases, including SLE. 3,4,23,24 In this study, we also found a higher frequency of cTfh cells in SLE patients than in HS. Moreover, we showed that patients with clearly active disease had increased cTfh cells than patients with mildly active/nonactive disease.…”

Follicular Helper T Cells and Autoimmune Diseases

“…Compared with healthy people, the proportion of cTfh17 cells in SLE patients is increased [37]. However, Szabó et al found that the frequency of cTfh17 cells decreased in patients with lupus nephritis, which is related to higher disease activity scores [38]. These different results may be due to the use of different markers to detect cTfh17 cells.…”

Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

“…Its receptor IL-21R is abundantly expressed in a variety of immune cells. 118,119 Importantly, a study by Zhou t al. in 2023 showed that IL-21 has prominent antitumor effects in tumors.…”

“…IL‐21 belongs to the common γ‐chain (γc) receptor cytokine family. Its receptor IL‐21R is abundantly expressed in a variety of immune cells 118,119 . Importantly, a study by Zhou t al.…”