The Absolute Number of circulating Treg cells are reduced in difficultto-treat RA Patients and are ameliorated by low-dose IL-2

Huanhuan Yan ¹ Xiaoyu Zi ¹ Huer Yan ² Xiaoying Zhang ¹ Jie Bai ¹ Chong Gao ³ Xiao-Feng Li ¹ Caihong Wang ^1*

• ¹ Second Hospital of Shanxi Medical University, Taiyuan, China
• ² Shanxi Medical University, Taiyuan, Shanxi Province, China
• ³ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Objective: Circulating regulatory T cells (Treg) are closely related to immune tolerance and maintenance of immune homeostasis. Maybe there is a unique immune cell phenotype for Difficult-totreat rheumatoid arthritis (D2T RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of autoimmune diseases. This study focused on the uniqueness of D2T RA lymphocyte subsets and the feasibility of low-dose IL-2 therapy.Methods: Participants included 1042 RA patients who were divided into three groups according to the presence or absence of treatment and their response to treatment in the last 6 months: Newly group, Treated group, and D2T group, and 339 healthy controls (HCs). Participants included 1042 patients with RA and 339 healthy controls (HCs). 381 patients with RA A total of 381 patients with 107, 151 and 123 in each of the three experimental groups were received low-dose IL-2 treatment (0.5 million international units (MIU) per day, subcutaneous injection from day 1 to day 5 from day 1 to day 5).Absolute numbers of peripheral blood lymphocyte subsets were detected by flow cytometry (FCM), and serum cytokine levels by flow cytometry bead array (CBA).The absolute number of T, CD4+T and Treg cells in D2T RA group was lower than that in Hc, Newly and Treated RA. Compared with Hc and Newly RA group, the ratio of Th17/Treg cells in D2T RA group increased. In terms of cytokine levels, Newly, Treated and D2T RA groups were higher than Hc. The number of Treg cells in RA patients was negatively correlated with the disease activity index. Treg cells in Newly, Treated and D2T RA groups could be increased by low-dose IL-2 therapy without any side effects.The number of lymphocytes and subsets in D2T RA patients was reduced, especially Treg cells, resulting in a shift in the balance of effector T cells /Treg cells toward effector T cells, which is ameliorated by low-dose IL-2 without obvious side effects.