Stat5 Phosphorylation In Cd4 T Cells From Patients With Sle Is Related To Changes In Their Subsets And Follow-Up Disease Severity

Activation of the STAT5 signaling pathway up-regulates antiapoptotic protein Bcl2 and drives proliferation of autoreactive conventional CD4 T cells (T-cons). In systemic lupus erythematosus (SLE), an increased T cell Bcl2 content and perturbed homeostasis of CD45RA(-)FOXP3(hi) activated regulatory T cells (aT(regs)) were described. We assessed T-con/T-reg subsets and phosphorylation of STAT5 (pSTAT5) in blood T cells from patients with SLE by using conventional and imaging flow cytometry. Forty-one patients with SLE, 33 healthy controls, and 29 patients with rheumatoid arthritis were included. Long-term monitoring was performed in 39 patients with SLE, which were followed longitudinally for up to 1000 d. Significantly increased Bcl2 protein content in T cells from patients with SLE was associated with IL-7-dependent STAT5 activation, expressed as increased basal levels and nuclear localization of pSTAT5. pSTAT5 levels were significantly increased in the FOXP3 low-expressing CD4(+) T cell subsets but not in the aT(reg) subset, which was significantly decreased in patients with SLE. In contrast to aT(reg), SLE T-con displayed significantly increased pSTAT5 and Bcl2 levels. Moreover, the percentage of T-con-expressing proliferation marker Ki-67 was significantly increased in patients with SLE and was positively correlated with CD4 T cell pSTAT5 levels. Finally, a subgroup of patients characterized by an increased T-con-pSTAT5/aT(reg)-pSTAT5 ratio experienced a more aggressive-relapsing disease course and displayed higher time-adjusted cumulative CD4 T cell pSTAT5 levels during follow-up, which were positively correlated with time-adjusted cumulative disease activity. Our results indicate that imbalanced STAT5 phosphorylation, which is related to Bcl2 and Ki-67 expression, may confer survival and proliferative advantage to T-con over aT(reg) and could represent a possible marker of SLE disease severity.