No abstract

Myeloid-derived suppressor cells (MDSCs) are well known regulators of regulatory T cells (Treg cells); however, the direct regulation of MDSCs by Treg cells has not been well characterized. We find that colitis caused by functional deficiency of Treg cells leads to altered expansion and reduced function of MDSCs. During differentiation of MDSCs in vitro from bone marrow cells, Treg cells enhanced MDSC function and controlled their differentiation through a mechanism involving transforming growth factor-β (TGF-β). TGF-β-deficient Treg cells were not able to regulate MDSC function in an experimentally induced model of colitis. Finally, we evaluated the therapeutic effect of TGF-β-mediated in-vitro-differentiated MDSCs on colitis. Adoptive transfer of MDSCs that differentiated with TGF-β led to better colitis prevention than the transfer of MDSCs that differentiated without TGF-β. Our results demonstrate an interaction between Treg cells and MDSCs that contributes to the regulation of MDSC proliferation and the acquisition of immunosuppressive functions.

Myeloid-derived suppressor cells (MDSCs) regulate T cell immunity, and this population is a new therapeutic target for immune regulation. A previous study showed that transforming growth factor-β (TGF-β) is involved in controlling MDSC differentiation and immunoregulatory function in vivo. However, the direct effect of TGF-β on MDSCs with various cytokines has not previously been tested. Thus, we examined the effect of various cytokine combinations with TGF-β on MDSCs derived from bone marrow cells. The data show that different cytokine combinations affect the differentiation and immunosuppressive functions of MDSCs in different ways. In the presence of TGF-β, interleukin-6 (IL-6) was the most potent enhancer of MDSC function, whereas granulocyte colony-stimulating factors (G-CSF) was the most potent in the absence of TGF-β. In addition, IL-4 maintained MDSCs in an immature state with an increased expression of arginase 1 (Arg1). However, regardless of the cytokine combinations, TGF-β increased expansion of the monocytic MDSC (Mo-MDSC) population, expression of immunosuppressive molecules by MDSCs, and the ability of MDSCs to suppress CD4+ T cell proliferation. Thus, although different cytokine combinations affected the MDSCs in different ways, TGF-β directly affects monocytic-MDSCs (Mo-MDSCs) expansion and MDSCs functions.

An 8-week feeding trial was conducted to study the effect of dietary supplementation of a biofloc powder on growth performance and non-specific immune response of Litopenaeus vannamei. Seven experimental diets were prepared with supplementation of graded levels of dried biofloc powder by 0, 0.5, 1.0, 2.0, 4.0, 6.0, and 8.0% (designated as Con, BF0.5, BF1, BF2, BF4, BF6, and BF8, respectively). Triplicate groups of shrimp (1.01 ± 0.01 g) were hand-fed with one of the diets four times a day. At the end of the feeding trial, significantly (P ˂ 0.05) higher growth performance and feed utilization were obtained in BF4 groups compared to those fed the Con diet. The innate immunity of shrimp was improved by the dietary supplementation of biofloc. Dietary inclusion of biofloc at the level of 4.0% significantly increased disease resistance of shrimp against Vibrio harveyi. The results indicate that biofloc might be used as a dietary supplement for growth performance, innate immunity and disease resistance of Pacific white shrimp.

A study of three feeding trials was conducted to investigate the dietary protein requirements of Pacific white shrimp (Litopenaeus vannamei) at three different growth stages. Six experimental diets were formulated to include increasing protein levels of 25, 30, 35, 40, 45, and 50% (designated as P25, P30, P35, P40, P45, and P50, respectively) for three feeding trials. The three feeding trials were conducted in different-sized shrimp at 0.65 g (trial 1), 4.80 g (trial 2), and 10.5 g (trial 3). Triplicate groups of shrimp were fed one of the experimental diets for 36, 42, and 48 days in trials 1, 2, and 3, respectively. In trial 1, the growth performance was not affected by the dietary protein levels. However, protein efficiency ratio was significantly higher in P30 diet compared to P40, P45, and P50 diets. In trial 2, growth rate was significantly higher in P35 diet than in P25 diet. In trial 3, the lowest growth performance was obtained in P25 diet which significantly differed from that of other experimental diets. Broken line analysis of growth data indicates that the optimal dietary level of crude protein is 34.5, 35.6, and 32.2% for small-, medium-, and large-sized (juvenile, sub-adult, and adult stages) Pacific white shrimp, respectively.

The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4+ T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Consequently, in the absence of CRBN, the expression of Kv1.3 is derepressed, resulting in increased Kv1.3 expression, potassium flux, and CD4+ T-cell hyperactivation. In addition, experimental autoimmune encephalomyelitis in T-cell–specific Crbn-deficient mice was exacerbated by increased T-cell activation via Kv1.3. Thus, CRBN limits CD4+ T-cell activation via epigenetic regulation of Kv1.3 expression.

Phosphoinositide-dependent kinase 1 (PDK1) plays an important role in integrating the T cell antigen receptor (TCR) and CD28 signals to achieve efficient NF-κB activation. PDK1 is also an important regulator of T cell development, mediating pre-TCR induced proliferation signals. However, the role of PDK1 in B cell antigen receptor (BCR) signaling and B cell development remains largely unknown. In this study we provide genetic evidence supporting the role of PDK1 in B cell survival. We found PDK1 is required for BCR mediated survival in resting B cells, likely through regulation of Foxo activation. PDK1-dependent signaling to NF-κB is not crucial to resting B cell viability. However, PDK1 is necessary for triggering NF-κB during B cell activation and is required for activated B cell survival. Together these studies demonstrate that PDK1 is essential for BCR-induced signal transduction to Foxo and NF-κB and is indispensable for both resting and activated B cell survival.

This study calculates the vertical diffusivity and the fluxes of heat, salt, and buoyancy due to turbulence and double diffusion based on a 14 day time series of observations of the dissipation rates of turbulent kinetic energy and thermal variance at 0°N, 156°E from 25 October to 18 November 2012. Salt fingering dominates shear-driven turbulence below 100 m. The estimated flux and associated vertical diffusivity due to double diffusion are approximately 1 order of magnitude higher for temperature and density and 2 orders of magnitude higher for salinity compared to values calculated from a turbulence model. Under weak turbulence conditions, the turbulence model significantly underestimates the magnitude of the vertical buoyancy flux with the flux having the wrong sign. Under these conditions, fluxes induced by double-diffusive mixing need to be considered.