Interleukin-2 Deprived State of Regulatory T cells and Their Recovery by Low-Dose Interleukin-2 in Patients With...

Regeneration and expansion of Treg by low-dose interleukin-2 (IL-2) therapy is considered a potential treatment strategy for a wide range of autoimmune diseases. To provide a pathophysiologically-based rationale for low-dose IL-2 therapy, we investigated whether reversible defects in the Treg-IL-2 axis emerge in inflammatory myopathies.

CD4+ T cell subsets from patients with polymyositis (PM) or dermatomyositis (DM) (n = 20) and healthy controls (HC) (n = 19) and peripheral blood mononuclear cells (PBMC) from eight patients that were stimulated in vitro for 24 hours with different concentrations of recombinant human IL-2 were analyzed by multicolor flow cytometry. Messenger RNA (mRNA) expressions of IL2RA, IL2RB, IL2RB, ENTPD1, IKZF2, and CTLA4 were quantified by real-time polymerase chain reaction in IL-2 stimulated PBMC (n = 6). Two patients with refractory PM/DM were treated with low-dose IL-2 therapy for eight weeks and monitored for clinical responses and changes in Treg subsets.

Frequencies of Treg expressing CD25 at high levels (CD25hi Treg) and of CXCR5+ Treg were reduced in patients with PM/DM compared with HC (P = 0.0052; P = 0.0661), particularly in active myositis (P = 0.0036; P = 0.0335). Stimulation with low doses of IL-2 selectively enhanced expression of CD25 molecules by Treg, leading to an increase in the CD25hi Treg subset (P < 0.05) and augmented mRNA expression of several immunoregulatory molecules (P < 0.05). Low-dose IL-2 therapy induced decreases in muscle enzymes that were accompanied by a sustained expansion of CD25+ Treg.

Our data suggest that shortage of IL-2 is pathophysiologically relevant in PM/DM. Recovery and expansion of Treg by low-dose IL-2 therapy could thus be a promising targeted treatment option.