Objective <p>This study is aimed at investigating the characteristics of RA patients at different stages and at evaluating the potential application of low-dose interleukin-2 (ld-IL-2) during the preclinical stage.</p> Methods <p>Patients with undifferentiated arthritis (UA), early RA (Ea-RA), new-onset RA (New-RA), and recurrent RA (Re-RA) were included. Clinical data and laboratory parameters were collected from all participants. A comparative analysis of arthritis-related clinical features and serum levels of IL-2 and soluble IL-2 receptor (sIL-2R) was conducted. Collagen-induced arthritis (CIA) mice received ld-IL-2 on days 0, 7, 14, and 28 after primary immunisation for 4&#xa0;weeks. The percentages of Treg, Tfr, Tfh, and PD-1⁺Tfh cells were analysed. Additionally, naive CD4⁺ T cells were cultured in vitro to assess the effects of IL-2 on Tfh and Tfr differentiation.</p> Results <p>UA patients primarily exhibited early involvement of large joints. The sIL-2R level in UA patients was significantly lower than in those with Ea-RA, New-RA, and Re-RA and was comparable to levels in healthy controls. ld-IL-2 administration at different time points in the CIA model exerted varying effects on arthritis severity. Prophylactic ld-IL-2 administration reduced arthritis severity and incidence in CIA; it decreased the percentage of PD-1⁺Tfh cells while increasing Tfr cells, thereby restoring immune balance. All IL-2 intervention groups effectively reduced the Tfh/Tfr ratio and altered the distribution of B cell subsets. Mechanistically, ld-IL-2 primarily suppressed the differentiation of PD-1⁺Tfh cells and promoted Treg cell differentiation via STAT3 and STAT5 signalling, contributing to the restoration of immune tolerance.</p> Conclusion <p>These findings indicate that elevated sIL-2R levels in UA patients may predict progression to Ea-RA. Furthermore, ld-IL-2 restores immune tolerance by rebalancing Tfh/Tfr populations, highlighting its potential as a novel immunoregulatory strategy during the preclinical phase of RA.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p>Key Points</p> <p>• <i>Prophylactic low-dose IL-2 intervention reduces the severity and incidence of arthritis in the CIA model.</i></p> <p>• <i>Low-dose IL-2 decreases the percentage of PD-1</i>⁺<i>Tfh cells while increasing Tfr cells, contributing to the restoration of immune balance.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>