Competitive binding of transcription factors underlies flexibility of T peripheral helper cells and T follicular helper cells in SLE

Abstract

Objective Peripheral helper T (Tph) cells interact with B cells and promote immune responses at sites of ectopic lymphoid structures (ELSs). To assess the characteristics of Tph cells, we investigated the phenotype of T helper (Th) cells in patients with systemic lupus erythematosus (SLE) and the underlying competitive binding mechanisms using cytokines-mediated signal transducer and activator of transcription (STAT) factors. Methods Peripheral blood mononuclear cells from SLE patients and healthy controls were analyzed for phenotype identifying. Serum cytokine levels were detected using Luminex assays. In vitro culture was performed to assess cytokine-induced conversion of phenotypes and transcriptional regulation using flow cytometry and PCR. Chromatin immunoprecipitation was used to evaluate STATs binding and histone modifications. Results CXCR5-PD-1+Tph-like cells were increased in SLE patients and showed strong association with disease activity and renal involvement. Serum IFN-α levels were increased and associated with Tph frequency. IFN-α promoted the differentiation of IL-10-producing CXCR5-PD-1+Tph-like cells, increased the responsiveness of IL-2, and induced the conversion of Tfh-like cells to Tph-like cells. STAT5 gained advantage and bound to BCL6 locus at expense of STAT1, accompanied by suppression of H3K4me3. Finally, anti-IFNAR1 decreased the differentiation of Tph-like cells, thereby suppressing the generation of CD38highCD27highplasmablasts. Conclusion Tph cells might be crucial makers to effectively reflect disease activity level in SLE patients. The finding that synergy of IFN-α and IL-2 increases Tph cells through competitive transcriptional regulation, could be one of the mechanisms responsible for pathologic formation of ELSs and helpful for selection of individualized therapeutic approaches for SLE.

T peripheral helper cells in autoimmune diseases: What do we know?

“…Mounting studies have been conducted to investigate the physiological role and mechanisms of Tph cells, predominantly focusing on autoimmune diseases (shown in Table 1), including RA (6,7,48,(52)(53)(54), SLE (26, [55][56][57][58][59][60][61], SS (62-66), IgG4-related disease (IgG4-RD) (64, 67), type 1 diabetes (T1D) (68, 69), primary biliary cirrhosis (PBC) (70), immunoglobulin A nephropathy (IgAN) (71), juvenile idiopathic arthritis (JIA) (72), autoimmune hepatitis (AIH) (73), dermatomyositis (DM) (74), celiac disease (CeD) (58), systemic sclerosis (SSc) (58), autoimmune bowel disease (IBD) (75), and psoriasis vulgaris (PV) (76). Notably, most studies elucidated altered frequencies of Tph cells and their correlation with disease activity, and they analyzed only cTph cells because of the relative difficulty in obtaining tissue samples.…”

“…SLE is an autoimmune connective-tissue disorder which is characterized by loss of self-tolerance and formation of nuclear autoantigens and immune complexes with great clinical heterogeneity ( 78 ). Tph cells were found to be enlarged in peripheral blood from SLE patients ( 26 , 55 – 57 , 59 , 60 ) and in tubulointerstitial areas from patients with proliferative lupus nephritis ( 57 ). Four out of ten patients with SLE showed significantly elevated numbers of cTph cells ( 58 ).…”

Review on the Use of Satellite-Based Radar Interferometry for Monitoring Mining Subsidence in Urban Areas and Demographic Indicators Assessment

“…salt mine in Poland [11][12][13]),  active mining sites (e.g. coal mine in Gardanne France [24], Rydultowy, Poland [28], Legnica Glogow Cooper Belt, Poland [46], New South Wales Australia coal mine [29,30], El Teniente, Chile [39,44], China [20,37,38,49])  mining sites with historical and active mines (e.g. Ruhr region, Germany [33])…”

“…One of the limitations of this technique is related to the presence of the atmospheric effect in the final result [23]. DInSAR was used for mining subsidence monitoring in [10,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38].…”

Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation

“…Therefore, it is likely that restriction of E protein binding to the “right” set of mediators within each lineage is essential for linking environmental input to functional output in Th subsets. This is clearly a strong paradigm for peripheral T cell differentiation ( 27 ). The Clutch model also applies to T cell development in the thymus, but with a twist, as described below ( Figure 1B ).…”