Macrophage and T cell networks in adipose tissue.

The signals and structure of the tissues in which leukocytes reside critically mould leukocyte function and development and have challenged our fundamental understanding of how to define and categorize tissue-resident immune cells. One specialized tissue niche that has a powerful effect on immune cell function is adipose tissue. The field of adipose tissue leukocyte biology has expanded dramatically and has revealed how tissue niches can shape immune cell function and reshape them in a setting of metabolic stress, such as obesity. Most notably, adipose tissue macrophages and T cells are under intense investigation due to their contributions to adipose tissue in the lean and obese states. Both adipose tissue macrophages and T cells have features associated with the metabolic function of adipose tissue that are distinct from features of macrophages and T cells that are classically characterized in other tissues. This Review provides state-of-the-art understanding of adipose tissue macrophages and T cells and discusses how their unique niche can help us to better understand diversity in leukocyte responses.

Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment.

The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that undergo pathophysiological reprogramming in disease states, such as non-alcoholic steatohepatitis (NASH). Patients with NASH are at an increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here, we show that diet-induced NASH is characterized by the induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic CD8+ T cells in the liver. The adipocyte-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbated the induction of tumor-prone liver immune microenvironment and NASH-related HCC, whereas transgenic NRG4 overexpression elicited protective effects in mice. In a therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potency in suppressing HCC and prolonged survival in the treated mice. These findings pave the way for therapeutic intervention of liver cancer by targeting the NRG4 hormonal checkpoint.

Cell intrinsic characteristics of human cord blood naïve CD4T cells.

It has been generally considered that the perinatal immune system is less inflammatory compared to the adult system and type 2 responses predominate perinatal immune responses against antigens. Indeed, previous studies in mice showed that there are cell-intrinsic differences between neonatal and adult CD4T cells. However, studies on human cord blood and infant blood demonstrated that human perinatal T cells do not produce elevated levels of Th2 cytokines with the exception of IL-13. These data raise the question if human T cells in the perinatal blood fundamentally differ from adult T cells. To decipher differences between human perinatal and adult T cells, we performed a focused comparative analysis on purified naïve CD4T cells from umbilical cord blood (UCB) and adult peripheral blood. Our data demonstrate naïve CD4T cells from UCB differ from adult naïve CD4T cells in surface expression of CD26, dipeptidyl peptidase-4. While only a fraction of effector/memory T cells from adult blood express CD26, practically all T cells from UCB express high levels of CD26. We also determined that Th1/Th2 polarizing conditions induce UCB CD4T cells to produce higher levels of IFN-γ and IL-5 compared to adult CD4T cells, respectively. These data demonstrate intrinsic differences between UCB and adult naive CD4T cells and suggest that human perinatal immune responses involve more complex mechanisms than the previously thought Th2-dominant responses.

The effect of sugar removal on the structure of the Fc region of an IgG antibody as observed with single molecule Förster Resonance Energy Transfer.

The deglycosylation of immunoglobulin G (IgG) antibodies leads to a diminished immune response. This reduction in immune response is thought to arise from weakened binding of IgG antibodies to effector molecules as a result of a conformational change in the antibody. The nature of this structural alteration is uncertain due to the conflicting results obtained from different experimental methods. We have examined the impact of deglycosylation by the endoglycosidase PNGase F on the structure of the Fc region of a human IgG antibody using single molecule Förster Resonance Energy Transfer (FRET). The FRET efficiency histograms obtained indicate that the structure of the Fc region becomes more flexible upon deglycosylation. This is demonstrated by a change in the width of the energy transfer efficiency peak, which increases from 0.19 ± 0.02 to 0.6 ± 0.1 upon deglycosylation.