Cutting Edge: Bach2 Integrates Cytokine Signals to Arbitrate Differentiation Decisions between T Follicular Helper and Th17 Lineages.

CXCR5 is a hallmark of T follicular helper (Tfh) cells. The mechanism of CXCR5 induction, however, is still incompletely understood. In this study, we report that in mice with the absence of transcription factor Bach2, the Th17-inducing cytokines IL-6 and TGF-ß together induced CXCR5 expression in vitro. Mechanistically, IL-6/STAT3 drove Cxcr5 promoter activity via the upstream site 1 regulatory element, whereas TGF-ß enhanced permissive histone modifications, and the STAT3 binding to the site 1 regulatory element was higher in the absence of Bach2. Subsequently, despite previous studies showing enhanced Th17 cell differentiation in the absence of Bach2 in vitro, we found that in vivo, the Bach2 deficiency led to an enhanced Tfh cell response at the expense of the Th17 cell response. These findings suggest that Bach2 helps integrate cytokine signals to arbitrate differentiation decisions between Tfh and Th17 lineages.

The Synthesis and Characterization of Highly Fluorescent Polycyclic Azaborine Chromophores.

Six new heteroaromatic polycyclic azaborine chromophores were designed, synthesized, and investigated as easily tunable high-luminescent organic materials. The impact of the nitrogen-boron-hydroxy (N-BOH) unit in the azaborines was investigated by comparison with their N-carbonyl analogs. Insertion of the N-B(OH)-C unit into heteroaromatic polycyclic compounds resulted in strong visible absorption and sharp fluorescence with efficient quantum yields. The solid-state fluorescence of the heteroaromatic polycyclic compounds displayed a large Stokes shift compared to being in solution. The large Stokes shifts observed offset the self-quench effect in the solid state.

Aortic valve replacement reduces valvuloarterial impedance but does not affect systemic arterial compliance in elderly men with degenerative calcific trileaflet aortic valve stenosis.

OBJECTIVE: Standard methods of quantifying aortic valve stenosis (AS), which focus entirely on the valve itself, do not adequately characterize the magnitude, predict the onset, progression, and severity of symptoms, or identify the incidence of subsequent adverse events. Valvuloarterial impedance (Z(va)) is an index of global left ventricular (LV) afterload that incorporates valvular and arterial loads. The authors tested the hypothesis that aortic valve replacement (AVR) reduces Z(va) but does not affect the arterial component of LV afterload in elderly patients with degenerative calcific trileaflet AS. DESIGN: Observational study. SETTING: Veterans affairs medical center. PARTICIPANTS: Eight elderly (age, 79 ± 4 years) men with moderate-to-severe AS and normal preoperative LV function (ejection fraction, 61% ± 9%) scheduled for AVR with or without coronary artery bypass graft surgery were studied after institutional review board approval. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A comprehensive TEE examination was performed during isoflurane-fentanyl-rocuronium anesthesia. Doppler echocardiography was used to measure pressure gradients across the aortic valve, stroke volume (continuity equation), and aortic valve area using standard techniques. Z(va) was determined as (systolic arterial pressure+mean gradient)/stroke volume index. Energy loss index was calculated as (aortic area × aortic valve area)/([aortic area--aortic valve area]× body surface area). The stroke work loss was obtained as (mean gradient × 100/[systolic arterial pressure+mean gradient]). The ratio of stroke volume index to pulse pressure was used to measure systemic arterial compliance. Z(va), energy loss index, stroke work loss, and systemic arterial compliance were assessed before and 15 minutes after cardiopulmonary bypass. Systemic and pulmonary hemodynamics (invasive catheters) were similar after versus before AVR. Aortic valve area increased significantly (p<0.05) with AVR (0.92 ± 0.26 cm(2) to 1.94 ± 0.35 cm(2)), concomitant with decreases in peak and mean gradients (60 ± 17 mmHg to 15 ± 8 mmHg and 38 ± 11 mmHg to 8 ± 5 mmHg, respectively) and peak blood flow velocity (3.9 ± 0.5 m · s(-1) to 1.9 ± 0.5 m · s(-1)). AVR reduced Z(va) (4.6 ± 1.0 mmHg · mL(-1) · m(-2) to 3.5 ± 0.3 mmHg · mL(-1) · m(-2)) and improved energy loss index (0.55 ± 0.16 cm(2) · m(-2) to 1.58 ± 0.48 cm(2) · m(-2)) concomitant with a decline in stroke work loss (25% ± 6% to 7% ± 4%), but systemic arterial compliance remained unchanged (0.63 ± 0.13 compared with 0.70 ± 0.12 mL · mmHg(-1)· m(-2)). CONCLUSION: The current results showed that AVR acutely reduced Zva, improved energy loss index, and decreased stroke work loss, but did not affect systemic arterial compliance in elderly men with degenerative calcific trileaflet AS.

Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate.

Follicular helper T (Tfh) cells are essential for germinal center (GC) B cell responses. However, it is not clear which PD-1+CXCR5+Bcl6+CD4+ T cells will differentiate into PD-1hiCXCR5hiBcl6hi GC-Tfh cells and how GC-Tfh cell differentiation is regulated. Here, we report that the sustained Tigit expression in PD-1+CXCR5+CD4+ T cells marks the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit-PD-1+CXCR5+CD4+ T cells upregulate IL-7Rα to become CXCR5+CD4+ T memory cells with or without CCR7. We demonstrate that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. The transcription factor c-Maf appears critical in governing the pre-Tfh to GC-Tfh transition, and we identify Plekho1 as a stage-specific downstream factor regulating the GC-Tfh competitive fitness. In summary, our work identifies an important marker and regulatory mechanism of PD-1+CXCR5+CD4+ T cells during their developmental choice between memory T cell fate and GC-Tfh cell differentiation.

Stepwise Tfh cell differentiation revisited: new advances and long-standing questions.

T follicular helper (Tfh) cells play an essential role in germinal center formation and the generation of high-affinity antibodies. Studies have proposed that Tfh cell differentiation is a multi-step process. However, it is still not fully understood how a subset of activated CD4+ T cells begin to express CXCR5 during the early stage of the response and, shortly after, how some CXCR5+ precursor Tfh (pre-Tfh) cells enter B cell follicles and differentiate further into germinal center Tfh (GC-Tfh) cells while others have a different fate. In this mini-review, we summarize the recent advances surrounding these two aspects of Tfh cell differentiation and discuss related long-standing questions, including Tfh memory.