Recently published - More

Abstract

Patients with leukemia who receive a T cell–depleted allogeneic stem cell graft followed by postponed donor lymphocyte infusion (DLI) can experience graft-versus-leukemia (GVL) reactivity, with a lower risk of graft-versus-host disease (GVHD). Here, we have investigated the magnitude, diversity, and specificity of alloreactive CD8 T cells in patients who developed GVL reactivity after DLI in the absence or presence of GVHD. We observed a lower magnitude and diversity of CD8 T cells for minor histocompatibility antigens (MiHAs) in patients with selective GVL reactivity without GVHD. Furthermore, we demonstrated that MiHA-specific T cell clones from patients with selective GVL reactivity showed lower reactivity against nonhematopoietic cells, even when pretreated with inflammatory cytokines. Expression analysis of MiHA-encoding genes showed that similar types of antigens were recognized in both patient groups, but in patients who developed GVHD, T cell reactivity was skewed to target broadly expressed MiHAs. As an inflammatory environment can render nonhematopoietic cells susceptible to T cell recognition, prevention of such circumstances favors induction of selective GVL reactivity without development of GVHD.

Authors

Cornelis A.M. van Bergen, Simone A.P. van Luxemburg-Heijs, Liesbeth C. de Wreede, Matthijs Eefting, Peter A. von dem Borne, Peter van Balen, Mirjam H.M. Heemskerk, Arend Mulder, Fransiscus H.J. Claas, Marcelo A Navarrete, Wilhelmina M. Honders, Caroline E. Rutten, Hendrik Veelken, Inge Jedema, Constantijn J.M. Halkes, Marieke Griffioen, J.H. Frederik Falkenburg

×

Abstract

MicroRNAs (miRs) are tightly regulated in the immune system, and aberrant expression of miRs often results in hematopoietic malignancies and autoimmune diseases. Previously, it was suggested that elevated levels of miR-27 in T cells isolated from patients with multiple sclerosis facilitate disease progression by inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we have demonstrated that, although mice with T cell–specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell-autonomous manner. Rather, dysregulation of Th1 responses and autoimmunity resulted from a perturbed Treg compartment. Excessive miR-27 expression in murine T cells severely impaired Treg differentiation. Moreover, Tregs with exaggerated miR-27–mediated gene regulation exhibited diminished homeostasis and suppressor function in vivo. Mechanistically, we determined that miR-27 represses several known as well as previously uncharacterized targets that play critical roles in controlling multiple aspects of Treg biology. Collectively, our data show that miR-27 functions as a key regulator in Treg development and function and suggest that proper regulation of miR-27 is pivotal to safeguarding Treg-mediated immunological tolerance.

Authors

Leilani O. Cruz, Somaye Sadat Hashemifar, Cheng-Jang Wu, Sunglim Cho, Duc T. Nguyen, Ling-Li Lin, Aly Azeem Khan, Li-Fan Lu

×

Abstract

The BM niche comprises a tightly controlled microenvironment formed by specific tissue and cells that regulates the behavior of hematopoietic stem cells (HSCs). Here, we have provided a 3D model that is tunable in different BM niche components and useful, both in vitro and in vivo, for studying the maintenance of normal and malignant hematopoiesis. Using scaffolds, we tested the capacity of different stromal cell types to support human HSCs. Scaffolds coated with human mesenchymal stromal cells (hMSCs) proved to be superior in terms of HSC engraftment and long-term maintenance when implanted in vivo. Moreover, we found that hMSC-coated scaffolds can be modulated to form humanized bone tissue, which was also able to support human HSC engraftment. Importantly, hMSC-coated humanized scaffolds were able to support the growth of leukemia patient cells in vivo, including the growth of samples that would not engraft the BM of immunodeficient mice. These results demonstrate that an s.c. implantation approach in a 3D carrier scaffold seeded with stromal cells is an effective in vivo niche model for studying human hematopoiesis. The various niche components of this model can be changed depending on the context to improve the engraftment of nonengrafting acute myeloid leukemia (AML) samples.

Authors

Ander Abarrategi, Katie Foster, Ashley Hamilton, Syed A. Mian, Diana Passaro, John Gribben, Ghulam Mufti, Dominique Bonnet

×

Abstract

Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3′-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease. In a well-characterized mouse model for DM1 (HSALR mice), activation of AMPK signaling in muscle was impaired under starved conditions, while mTORC1 signaling remained active. In parallel, autophagic flux was perturbed in HSALR muscle and in cultured human DM1 myotubes. Pharmacological approaches targeting AMPK/mTORC1 signaling greatly ameliorated muscle function in HSALR mice. AICAR, an AMPK activator, led to a strong reduction of myotonia, which was accompanied by partial correction of misregulated alternative splicing. Rapamycin, an mTORC1 inhibitor, improved muscle relaxation and increased muscle force in HSALR mice without affecting splicing. These findings highlight the involvement of AMPK/mTORC1 deregulation in DM1 muscle pathophysiology and may open potential avenues for the treatment of this disease.

Authors

Marielle Brockhoff, Nathalie Rion, Kathrin Chojnowska, Tatiana Wiktorowicz, Christopher Eickhorst, Beat Erne, Stephan Frank, Corrado Angelini, Denis Furling, Markus A. Rüegg, Michael Sinnreich, Perrine Castets

×

Abstract

Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution. In human carotid plaques, MerTK cleavage correlated with plaque necrosis and the presence of ischemic symptoms. Moreover, in fat-fed LDL receptor–deficient (Ldlr–/–) mice whose myeloid cells expressed a cleavage-resistant variant of MerTK, atherosclerotic lesions exhibited higher macrophage MerTK, lower levels of the cleavage product soluble Mer, improved efferocytosis, smaller necrotic cores, thicker fibrous caps, and increased ratio of proresolving versus proinflammatory lipid mediators. These findings provide a plausible molecular-cellular mechanism that contributes to defective efferocytosis, plaque necrosis, and impaired resolution during the progression of atherosclerosis.

Authors

Bishuang Cai, Edward B. Thorp, Amanda C. Doran, Brian E. Sansbury, Mat J.A.P. Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira Tabas

×

Abstract

Failure of trabecular myocytes to undergo appropriate cell cycle withdrawal leads to ventricular noncompaction and heart failure. Signaling of growth factor receptor ERBB2 is critical for myocyte proliferation and trabeculation. However, the mechanisms underlying appropriate downregulation of trabecular ERBB2 signaling are little understood. Here, we have found that the endocytic adaptor proteins NUMB and NUMBL were required for downregulation of ERBB2 signaling in maturing trabeculae. Loss of NUMB and NUMBL resulted in a partial block of late endosome formation, resulting in sustained ERBB2 signaling and STAT5 activation. Unexpectedly, activated STAT5 overrode Hippo-mediated inhibition and drove YAP1 to the nucleus. Consequent aberrant cardiomyocyte proliferation resulted in ventricular noncompaction that was markedly rescued by heterozygous loss of function of either ERBB2 or YAP1. Further investigations revealed that NUMB and NUMBL interacted with small GTPase Rab7 to transition ERBB2 from early to late endosome for degradation. Our studies provide insight into mechanisms by which NUMB and NUMBL promote cardiomyocyte cell cycle withdrawal and highlight previously unsuspected connections between pathways that are important for cardiomyocyte cell cycle reentry, with relevance to ventricular noncompaction cardiomyopathy and regenerative medicine.

Authors

Maretoshi Hirai, Yoh Arita, C. Jane McGlade, Kuo-Fen Lee, Ju Chen, Sylvia M. Evans

×



Advertisement

January 2017

127 1 cover

January 2017 Issue

On the cover:
Metastatic vesicle trafficking in EMT

Tan et al. uncover a role for Golgi apparatus compaction in regulating secretory vesicle trafficking during metastatic epithelial-to-mesenchymal transition. The cover image shows a normal bronchus within a human lung adenocarcinoma tissue section co-stained with DAPI (magenta) and antibodies against the Golgi protein GM130 (yellow) and collagen I (blue).

×
Jci tm 2017 01

January 2017 JCI This Month

JCI This Month is a digest of the research, reviews, and other features published each month.

×

Review Series - More

Metabolism and Inflammation

Series edited by Alan Saltiel and Jerrold Olefsky

Metabolic syndrome compromises a constellation of conditions including central obesity, glucose intolerance, and dyslipidemia. These conditions enhance the risk of type 2 diabetes, cardiovascular disease, fatty liver/cirrhosis, hypertension, and cancer. The finding over 20 years ago that the inflammatory mediator TNF is overexpressed in adipose fundamentally changed our understanding of obesity and metabolic syndrome. We now know that metabolic syndrome in humans is characterized by chronic low-grade inflammation in multiple organs and we are now beginning to delineate the mechanisms by which inflammation and metabolism influence each other. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a pro-inflammatory phenotype.

×