title: STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity.
abstract: Activation of the STAT5 signaling pathway up-regulates antiapoptotic protein Bcl2 and drives proliferation of autoreactive conventional CD4 T cells (Tcons). In systemic lupus erythematosus (SLE), an increased T cell Bcl2 content and perturbed homeostasis of CD45RA-FOXP3hiactivated regulatory T cells (aTregs) were described. We assessed Tcon/Tregsubsets 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 aTregsubset, which was significantly decreased in patients with SLE. In contrast to aTreg, SLE Tcondisplayed significantly increased pSTAT5 and Bcl2 levels. Moreover, the percentage of Tcon-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 Tcon-pSTAT5/aTreg-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 Tconover aTregand could represent a possible marker of SLE disease severity.
authors.affiliation: Department of Laboratory Diagnostics, University Medical Centre Maribor, Maribor, Slovenia; ales.goropevsek@ukc-mb.si.|Medical Faculty, University of Maribor, Maribor, Slovenia.
authors.forename: Aleš
authors.initials: A
authors.lastname: Goropevšek
authors.affiliation: Department of Laboratory Diagnostics, University Medical Centre Maribor, Maribor, Slovenia.
authors.forename: Maksimiljan
authors.initials: M
authors.lastname: Gorenjak
authors.affiliation: Department of Rheumatology, University Medical Centre Maribor, Maribor, Slovenia.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gradišnik
authors.affiliation: Department of Rheumatology, University Medical Centre Maribor, Maribor, Slovenia.
authors.forename: Klara
authors.initials: K
authors.lastname: Dai
authors.affiliation: Department of Rheumatology, University Medical Centre Maribor, Maribor, Slovenia.
authors.forename: Iztok
authors.initials: I
authors.lastname: Holc
authors.affiliation: Department of Nephrology, University Medical Centre Maribor, Maribor, Slovenia.
authors.forename: Radovan
authors.initials: R
authors.lastname: Hojs
authors.affiliation: Medical Faculty, University of Maribor, Maribor, Slovenia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Krajnc
authors.affiliation: Department of Rheumatology, University Medical Centre Maribor, Maribor, Slovenia.
authors.forename: Artur
authors.initials: A
authors.lastname: Pahor
authors.affiliation: Department of Allergology, Rheumatology, and Clinical Immunology, University Children's Hospital, University Medical Center Ljubljana, Ljubljana, Slovenia; and.|Medical Faculty, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Tadej
authors.initials: T
authors.lastname: Avčin
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D011379:Prognosis; D011446:Prospective Studies; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D012720:Severity of Illness Index; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050799:STAT5 Transcription Factor
keywords: cytokines; signal transduction; systemic lupus erythematosus