Sustained low‐dose interleukin‐2 therapy alleviates pathogenic humoral immunity via elevating the Tfr/Tfh ratio in lupus

Abstract

Objectives Low‐dose interleukin‐2 (IL‐2) has shown promising clinical benefits in the treatment of systemic lupus erythematosus (SLE), but how this therapy alleviates pathogenic humoral immunity remains not well understood. The dilemma is that IL‐2 can suppress both follicular helper and regulatory T (Tfh and Tfr) cells, which counteract each other in regulating autoantibody production. Methods Female NZB/W F1 mice received recombinant human IL‐2 (3 × 104 IU/dose) in three treatment regimens: (1) short, daily for 7 days; (2) medium, daily for 14 days, and (3) long, every second day for 28 days. Tfh (Foxp3−CXCR5+Bcl6+), Tfr (Foxp3+CXCR5+Bcl6+), germinal centre (GC, B220+GL‐7+Fas+) and antibody‐secreting cell (ASC, B220−CD138+TACI+) were analysed by flow cytometry. Serum anti‐dsDNA level was determined by ELISA. Kidney pathology was evaluated by H&E and immunofluorescence staining. Circulating Tfh and Tfr cells in SLE patients treated with low‐dose IL‐2 from a previous clinical trial (NCT02084238) was analysed. Results Low‐dose IL‐2 treatment consistently increased Tfr/Tfh ratio in mice and SLE patients, because of a stronger suppression on Tfh cells than Tfr cells. Three treatment regimens revealed distinct immunological features. Tfh suppression was observed in all regimens, but Tfr suppression and GC reduction were recorded in just medium and long regimens. Only the long treatment regimen resulted in inhibited ASC differentiation in spleen, which was accompanied by reduced anti‐dsDNA titres and ameliorated kidney pathology. Conclusion Low‐dose IL‐2 therapy increases the Tfr/Tfh ratio, and a less frequent and prolonged treatment can alleviate pathogenic humoral immunity and improve renal function.

Aberrant expansion of follicular helper T cell subsets in patients with systemic lupus erythematosus

“…First, the total number of specimens from outpatients with SLE, especially those with active SLE, is limited because the cohort of active SLE patients without drug therapy at the time of study enrolment is small. Several studies have demonstrated that drug treatments can affect cTfh cell frequencies (23,31,41). Therefore, a larger cohort will be investigated to clarify the role of cTfh cell subsets in SLE patients in the future.…”

“…Thirty outpatients with SLE and twenty-four age-and sexmatched healthy controls (HCs) were enrolled in the study. SLE patients were recruited according to the American College of Rheumatology criteria for the classification of SLE (23), and the exclusion criteria included therapy with immunosuppressive/ immunomodulant agents. The SLE Disease Activity Index (SLEDAI) scoring system was used to evaluate clinical disease activity, patients were classified according to having inactive or active disease status: the SLEDAI < 6 group comprised subjects with inactive disease (n=17), while SLEDAI ≧ 6 group consisted of subjects with active disease (n=13).…”

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

“…A balanced IL-2/CD25 signaling is critical for maintaining not just T FR but also T FH generation, because IL-2 could suppress both cells; nevertheless, it is required for Treg development. Two studies demonstrated that a carefully adjusted, prolonged low-dose IL-2 treatment led to the recovery of T FR /T FH immune balance and successfully mitigated pathogenic B cell responses, as well as kidney damage [ 50 , 51 ]. All these results support the use of T FR cells as an attractive therapeutic target in lupus.…”

Follicular Helper T Cells in the Immunopathogenesis of SARS-CoV-2 Infection

“…HighPD-1 expression on Tfh cells can significantly promote the differentiation and activity of Tfh cells (48)(49)(50). Collectively, Tfh cells are commonly identified as having three phenotypes: canonical GC Tfh cells with PD-1 ++ and ICOS ++ Bcl-6 + CCR7 -CXCR5 ++ CD4 + T cells, precursor-Tfh (Pre-Tfh) cells characterized as PD-1 + ICOS + Bcl-6 low CCR7 low CXCR5 + CD4 + T cells, and memory Tfh cells similar to Pre-Tfh cells in lymphoid tissue (36,(50)(51)(52). In GC, Tfh cells are responsible for regulating B cell differentiation into memory B cells and plasma cells, controlling the selection of high-affinity antibody production and the development of long-term humoral immunity (53)(54)(55)(56).…”