Also in this issue:

Quorum sensing among T cell subsets 9

miR-155 mediates B cell affinity maturation 9

Adenosine promotes endometrial tumor progression 10

Endothelial LRP1 clears amyloid-β 11

A summary of the current issue ofthe Journal of Clinical investigation

January 2016

jci.org/this-monthScan with your mobile device for the digital version of JCI This Month.

This MonthThis Month

Keeping time in cartilagep. 6

Keeping time in cartilagep. 6

http://www.HarringtonDiscovery.org/ThePrize

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This MonthJanuary 2016

editorHoward A. Rockman

Deputy editorsGarnett Kelsoe, Bryan L. Roth

Associate editorsSoman N. Abraham, Vann Bennett,Gerard C. Blobe, Kathleen M. Caron,Marc G. Caron, John P. Chute,Thomas M. Coffman, Anna Mae Diehl,Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Yiping Yang

Clinical Medicine Associate editorsMichael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy

Asia editorDavid M. Virshup

Chair, executive CouncilRobert J. Lefkowitz

BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen

BioethicistArthur L. Caplan

executive editorSarah C. Jackson

science editorsJillian Hurst, Corinne Williams

editor at largeUshma S. Neill

issn 2324-7703 (print)issn 2325-4556 (online)

The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

Contact the JCiThe Journal of Clinical Investigation2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: staff@the-jci.org

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New kid on the blockFrom the Editor

As Editor of the Journal of Clinical Investigation, I am pleased to announce the launch of a new journal called JCI Insight, which will publish well-executed, high-quality research across biomedicine that presents a focused yet insightful line of investigation. JCI Insight, published under an open-access model, represents an expansion of the American Society for Clinical Investigation’s longstanding commitment to disseminating preclinical, translational, and early-phase clinical research. JCI Insight will be a home for impactful biomedical studies that have potential for clinical translation and to spur subsequent research in the field.

In keeping with the editorial philosophy of the JCI, it is my intent to streamline peer review at JCI Insight so that is both rapid and fair. Requests for excessive additional experimentation will be discouraged; however, only rigorous and technically well-conducted science will be published. The JCI brand stands for excellence, and this is something on which I will not compromise.

We welcome submissions from all authors working in biomedical research, and while there will be no requirement for affiliation with the ASCI, active ASCI members will be granted three guaranteed external reviews per year for manuscripts that fit the scope of JCI Insight.

We look forward to serving our community of investigators with a new plat-form to disseminate their research ideas and discoveries. We believe that our future is bright and that we can continue the legacy created over 90 years ago by our Society.

For more information about submitting manuscripts to JCI Insight, please visit our website: www.insight.jci.org.

Howard A. RockmanEditor in Chief, The Journal of Clinical Investigation and JCI Insight

To read Dr. Rockman’s complete editorial, see http://jci.me/85448.

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Bone biologyThe chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrityMichal Dudek, Nicole Gossan, Nan Yang, Hee-Jeong Im, Jayalath P.D. Ruckshanthi, Hikari Yoshitane, Xin Li, Ding Jin, Ping Wang, Maya Boudiffa, Ilaria Bellantuono, Yoshitaka Fukada, Ray P. Boot-Handford, and Qing-Jun Meng http://jci.me/82755

With related Commentary by Karen M. Doody and Nunzio Bottini More, p. 6

CardiologyAberrant sodium influx causes cardiomyopathy and atrial fibrillation in miceElaine Wan, Jeffrey Abrams, Richard L. Weinberg, Alexander N. Katchman, Joseph Bayne, Sergey I. Zakharov, Lin Yang, John P. Morrow, Hasan Garan, and Steven O. Marx http://jci.me/84669

RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failureChen Gao, Shuxun Ren, Jae-Hyung Lee, Jinsong Qiu, Douglas J. Chapski, Christoph D. Rau, Yu Zhou, Maha Abdellatif, Astushi Nakano, Thomas M. Vondriska, Xinshu Xiao, Xiang-Dong Fu, Jau-Nian Chen, and Yibin Wang http://jci.me/84015

HematologyProgesterone receptor membrane component-1 regulates hepcidin biosynthesisXiang Li, David K. Rhee, Rajeev Malhotra, Claire Mayeur, Liam A. Hurst, Emily Ager, Georgia Shelton, Yael Kramer, David McCulloh, David Keefe, Kenneth D. Bloch, Donald B. Bloch, and Randall T. Peterson http://jci.me/83831

ImmunologyRituximab does not reset defective early B cell tolerance checkpointsNicolas Chamberlain, Christopher Massad, Tyler Oe, Tineke Cantaert, Kevan C. Herold, Eric Meffre, and the Type 1 Diabetes TrialNet Pathway to Prevention Study Group http://jci.me/83840

More, p. 8

Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cellsThamotharampillai Dileepan, Erica D. Smith, Daniel Knowland, Martin Hsu, Maryann Platt, Peter Bittner-Eddy, Brenda Cohen, Peter Southern, Elizabeth Latimer, Earl Harley, Dritan Agalliu, and P. Patrick Cleary http://jci.me/80792

More, p. 8

Research articles in the current issue of the JCI

Cartilage degeneration

MEF2-induced cardiac hypertrophy

GAS-induced synaptic changes

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Research articles in the current issue of the JCI

MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosisRinako Nakagawa, Rebecca Leyland, Michael Meyer-Hermann, Dong Lu, Martin Turner, Giuseppina Arbore, Tri Giang Phan, Robert Brink, and Elena Vigorito http://jci.me/82914

With related Commentary by Yee Ling Wu and Cristina Rada More, p. 9

Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapyChristopher A. Klebanoff, Christopher D. Scott, Anthony J. Leonardi, Tori N. Yamamoto, Anthony C. Cruz, Claudia Ouyang, Madhu Ramaswamy, Rahul Roychoudhuri, Yun Ji, Robert L. Eil, Madhusudhanan Sukumar, Joseph G. Crompton, Douglas C. Palmer, Zachary A. Borman, David Clever, Stacy K. Thomas, Shashankkumar Patel, Zhiya Yu, Pawel Muranski, Hui Liu, Ena Wang, Francesco M. Marincola, Alena Gros, Luca Gattinoni, Steven A. Rosenberg, Richard M. Siegel, and Nicholas P. Restifo http://jci.me/81217

With related Commentary by Yang Xu and Gianpietro Dotti More, p. 9

MetabolismCDK4 is an essential insulin effector in adipocytesSylviane Lagarrigue, Isabel C. Lopez-Mejia, Pierre-Damien Denechaud, Xavier Escoté, Judit Castillo-Armengol, Veronica Jimenez, Carine Chavey, Albert Giralt, Qiuwen Lai, Lianjun Zhang, Laia Martinez-Carreres, Brigitte Delacuisine, Jean-Sébastien Annicotte, Emilie Blanchet, Sébastien Huré, Anna Abella, Francisco J. Tinahones, Joan Vendrell, Pierre Dubus, Fatima Bosch, C. Ronald Kahn, and Lluis Fajas http://jci.me/81480

E2F1 mediates sustained lipogenesis and contributes to hepatic steatosisPierre-Damien Denechaud, Isabel C. Lopez-Mejia, Albert Giralt, Qiuwen Lai, Emilie Blanchet, Brigitte Delacuisine, Brandon N. Nicolay, Nicholas J. Dyson, Caroline Bonner, François Pattou, Jean-Sébastien Annicotte, and Lluis Fajas http://jci.me/81542

More, p. 12

Gq/11α and Gsα mediate distinct physiological responses to central melanocortinsYong-Qi Li, Yogendra Shrestha, Mritunjay Pandey, Min Chen, Ahmed Kablan, Oksana Gavrilova, Stefan Offermanns, and Lee S. Weinstein http://jci.me/76348

More, p. 12

Serum amyloid A impairs the antiinflammatory properties of HDLChang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O’Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. de Beer, Frederick C. de Beer, William R. Osborne, Keith B. Elkon, and Alan Chait http://jci.me/83475

More, p. 12

Muscle biologyPOPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein traffickingRoland F.R. Schindler, Chiara Scotton, Jianguo Zhang, Chiara Passarelli, Beatriz Ortiz-Bonnin, Subreena Simrick, Thorsten Schwerte, Kar-Lai Poon, Mingyan Fang, Susanne Rinné, Alexander Froese, Viacheslav O. Nikolaev, Christiane Grunert, Thomas Müller, Giorgio Tasca, Padmini Sarathchandra, Fabrizio Drago, Bruno Dallapiccola, Claudio Rapezzi, Eloisa Arbustini, Francesca Romana Di Raimo, Marcella Neri, Rita Selvatici, Francesca Gualandi, Fabiana Fattori, Antonello Pietrangelo, Wenyan Li, Hui Jiang, Xun Xu, Enrico Bertini, Niels Decher, Jun Wang, Thomas Brand, and Alessandra Ferlini http://jci.me/79562

IRS2 phosphorylation

Germinal center B cells

HDL on adipocytes

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Muscle biologyTRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesisSajedah M. Hindi and Ashok Kumar http://jci.me/81655

More, p. 7

Circulating protein synthesis rates reveal skeletal muscle proteome dynamicsMahalakshmi Shankaran, Chelsea L. King, Thomas E. Angel, William E. Holmes, Kelvin W. Li, Marc Colangelo, John C. Price, Scott M. Turner, Christopher Bell, Karyn L. Hamilton, Benjamin F. Miller, and Marc K. Hellerstein http://jci.me/79639

More, p. 7

NephrologyImmune activation caused by vascular oxidation promotes fibrosis and hypertensionJing Wu, Mohamed A. Saleh, Annet Kirabo, Hana A. Itani, Kim Ramil C. Montaniel, Liang Xiao, Wei Chen, Raymond L. Mernaugh, Hua Cai, Kenneth E. Bernstein, Jörg J. Goronzy, Cornelia M. Weyand, John A. Curci, Natalia R. Barbaro, Heitor Moreno, Sean S. Davies, L. Jackson Roberts II, Meena S. Madhur, and David G. Harrison http://jci.me/80761

NeuroscienceEndothelial LRP1 transports amyloid-β1–42 across the blood-brain barrierSteffen E. Storck, Sabrina Meister, Julius Nahrath, Julius N. Meißner, Nils Schubert, Alessandro Di Spiezio, Sandra Baches, Roosmarijn E. Vandenbroucke, Yvonne Bouter, Ingrid Prikulis, Carsten Korth, Sascha Weggen, Axel Heimann, Markus Schwaninger, Thomas A. Bayer, and Claus U. Pietrzik http://jci.me/81108

More, p. 11

OncologyHeparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activationTodd V. Brennan, Liwen Lin, Joshua D. Brandstadter, Victoria R. Rendell, Keith Dredge, Xiaopei Huang, and Yiping Yang http://jci.me/76566

More, p. 10

Genetic landscape of metastatic and recurrent head and neck squamous cell carcinomaMatthew L. Hedberg, Gerald Goh, Simion I. Chiosea, Julie E. Bauman, Maria L. Freilino, Yan Zeng, Lin Wang, Brenda B. Diergaarde, William E. Gooding, Vivian W.Y. Lui, Roy S. Herbst, Richard P. Lifton, and Jennifer R. Grandis http://jci.me/82066

MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancerMick D. Edmonds, Kelli L. Boyd, Tamara Moyo, Ramkrishna Mitra, Robert Duszynski, Maria Pia Arrate, Xi Chen, Zhongming Zhao, Timothy S. Blackwell, Thomas Andl, and Christine M. Eischen http://jci.me/82720

Loss of CD73-mediated actin polymerization promotes endometrial tumor progressionJessica L. Bowser, Michael R. Blackburn, Gregory L. Shipley, Jose G. Molina, Kenneth Dunner Jr., and Russell R. Broaddus http://jci.me/79380

More, p. 10

Research articles in the current issue of the JCI

TRAF6-depleted myocytes

Endothelial LRP1

Endometrial tumor CD73

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PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemiaChristopher B. Cole, Angela M. Verdoni, Shamika Ketkar, Elizabeth R. Leight, David A. Russler-Germain, Tamara L. Lamprecht, Ryan T. Demeter, Vincent Magrini, and Timothy J. Ley http://jci.me/82897

More, p. 11

SLAMF1 regulation of chemotaxis and autophagy determines CLL patient responseCinzia Bologna, Roberta Buonincontri, Sara Serra, Tiziana Vaisitti, Valentina Audrito, Davide Brusa, Andrea Pagnani, Marta Coscia, Giovanni D’Arena, Elisabetta Mereu, Roberto Piva, Richard R. Furman, Davide Rossi, Gianluca Gaidano, Cox Terhorst, and Silvia Deaglio http://jci.me/83013

Targeting ceramide synthase 6–dependent metastasis-prone phenotype in lung cancer cellsMotoshi Suzuki, Ke Cao, Seiichi Kato, Yuji Komizu, Naoki Mizutani, Kouji Tanaka, Chinatsu Arima, Mei Chee Tai, Kiyoshi Yanagisawa, Norie Togawa, Takahiro Shiraishi, Noriyasu Usami, Tetsuo Taniguchi, Takayuki Fukui, Kohei Yokoi, Keiko Wakahara, Yoshinori Hasegawa, Yukiko Mizutani, Yasuyuki Igarashi, Jin-ichi Inokuchi, Soichiro Iwaki, Satoshi Fujii, Akira Satou, Yoko Matsumoto, Ryuichi Ueoka, Keiko Tamiya-Koizumi, Takashi Murate, Mitsuhiro Nakamura, Mamoru Kyogashima, and Takashi Takahashi http://jci.me/79775

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma modelsAndrew W. Wong, Brett Z. Fite, Yu Liu, Azadeh Kheirolomoom, Jai W. Seo, Katherine D. Watson, Lisa M. Mahakian, Sarah M. Tam, Hua Zhang, Josquin Foiret, Alexander D. Borowsky, and Katherine W. Ferrara http://jci.me/83312

Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growthMichael Dewaele, Tommaso Tabaglio, Karen Willekens, Marco Bezzi, Shun Xie Teo, Diana H.P. Low, Cheryl M. Koh, Florian Rambow, Mark Fiers, Aljosja Rogiers, Enrico Radaelli, Muthafar Al-Haddawi, Soo Yong Tan, Els Hermans, Frederic Amant, Hualong Yan, Manikandan Lakshmanan, Ratnacaram Chandrahas Koumar, Soon Thye Lim, Frederick A. Derheimer, Robert M. Campbell, Zahid Bonday, Vinay Tergaonkar, Mark Shackleton, Christine Blattner, Jean-Christophe Marine, and Ernesto Guccione http://jci.me/82534

Research articles in the current issue of the JCI

SLAMF1-treated CLL

Necrotic tumor tissue

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A central clock in the suprachiasmatic nucleus of the hypothalamus controls many aspects of circadian timing; however, there is a growing appreciation of the importance of peripheral tissue clocks in regulating daily rhythms. In this month’s issue of the JCI, a research team led by Qing-Jun Meng and Ray Boot-Handford demonstrates that the circadian transcription factor BMAL1 plays an essential role in maintaining the integrity of cartilage tissue. They observed reduced numbers of BMAL1-expressing chondro-cytes in human articular cartilage tissue from osteo arthritic patients. Given this finding, they turned to a chondrocyte-specific Bmal1-KO mouse model and showed that these animals develop progressive degeneration of knee articular cartilage beginning at 2 months of age. RNA-sequencing analysis of chondrocytes in WT and KO animals revealed a network of genes regulated by Bmal1 in a circadian manner, including key regulators of carti-lage homeostasis. Components of both the TGF-β and NFAT signaling pathways, which have independently been shown to maintain cartilage integrity, were dysregulated in chondro-cytes from KO mice, resulting in decreased levels of the down-stream targets phosphorylated SMAD2 (p-SMAD2) and SOX9. In the related Commentary, Karen Doody and Nunzio Bottini discuss how these findings establish a critical link between chondrocyte BMAL1 expression and cartilage maintenance and the possible implication for degenerative joint diseases. The accompanying image shows degeneration in the knee joint articular cartilage of a 3-month-old chondrocyte- specific Bmal1-KO mouse.

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrityMichal Dudek, Nicole Gossan, Nan Yang, Hee-Jeong Im, Jayalath P.D. Ruckshanthi, Hikari Yoshitane, Xin Li, Ding Jin, Ping Wang, Maya Boudiffa, Ilaria Bellantuono, Yoshitaka Fukada, Ray P. Boot-Handford, and Qing-Jun Meng http://jci.me/82755

Related CommentaryChondrocyte clocks make cartilage time-sensitive materialKaren M. Doody and Nunzio Bottini http://jci.me/85632

Circadian rhythms in cartilage tissue regulate joint homeostasis

Editor’s picksResearch

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Research | Editor’s picks

muscle biology

A noninvasive method to measure skeletal muscle protein synthesis ratesloss of skeletal muscle mass in sarcopenia, cachexia, or atrophy is an important clinical problem, making it a target for drug develop-ment. Mahalakshmi Shankaran and colleagues report on a method to monitor skeletal muscle protein synthesis rates via a blood sample. Using heavy water labeling combined with tandem mass spectrometry, Shankaran and colleagues determined the fractional synthesis rate of plasma creatine kinase M-type and carbonic anhydrase-3, two proteins that are

synthesized almost entirely in muscle but escape into the circulation. Samples taken after sprint exercise training in humans or anabolic and catabolic interventions in rodents showed changes and interindividual differences in protein synthesis rates of these circulating proteins that were reflective of the entire muscle proteome, suggesting that this method could be used for rapid evaluation of therapeutic strategies to increase muscle mass or to prevent muscle wasting.

Circulating protein synthesis rates reveal skeletal muscle proteome dynamicsMahalakshmi Shankaran, Chelsea L. King, Thomas E. Angel, William E. Holmes, Kelvin W. Li, Marc Colangelo, John C. Price, Scott M. Turner, Christopher Bell, Karyn L. Hamilton, Benjamin F. Miller, and Marc K. Hellerstein http://jci.me/79639

TRAF6 maintains satellite cells for muscle regeneration

satellite cells mediate myofiber regeneration after muscle injury, and loss of these cells leads to decreased skeletal muscle mass. Sajedah M. Hindi and Ashok Kumar demonstrate that the adaptor protein and E3 ubiquitin ligase TRAF6 maintains satellite cell homeostasis and supports their regenerative functions. Satellite cell–specific deletion of Traf6 in adult mice caused profound defects in muscle regeneration (see the accompanying image) in both WT and dystrophic mice. Analysis of isolated myofibers showed that TRAF6 signaling activated ERK1/2 and JNK1/2 MAPK pathways to activate c-JUN and repress miR-1 and miR-206, thereby augmenting expression of PAX7, a transcription factor that is required for maintenance of satellite cells. Loss of TRAF6 markedly reduced PAX7 levels, leading to premature differentiation of satellite cells and impaired regeneration.

TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesisSajedah M. Hindi and Ashok Kumar http://jci.me/81655

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Research | Editor’s picks

immunology

Anti–B cell therapy does not alter tolerance checkpointstype 1 diabetes (t1D) and other autoimmune disorders are characterized by abnormalities in early B cell tolerance checkpoints that result in the accumulation of autoreactive B cells. The B cell–depleting mAb rituximab has been shown to preserve pancreatic β cell function in T1D, but the underlying mechanisms are unclear. Nicolas Chamberlain and colleagues analyzed the reactivity of Abs from single, mature naive B cells from 4 patients with T1D before and after 1 year of rituximab treatment. They found that rituximab treatment did not alter

the frequency of autoreactive and polyreactive B cells. Moreover, the self-reactive B cells were newly generated rather than the product of homeostatic expansion in the periphery, indicating that rituximab does not reset defective B cell tolerance checkpoints and possibly explaining why many patients relapse after discontinuation of therapy.

Rituximab does not reset defective early B cell tolerance checkpointsNicolas Chamberlain, Christopher Massad, Tyler Oe, Tineke Cantaert, Kevan C. Herold, Eric Meffre, and the Type 1 Diabetes TrialNet Pathway to Prevention Study Group http://jci.me/83840

Group A Streptococcus–specific Th17 cells mediate neurovascular damage

Group A streptococcal (GAs) infections are associated with autoimmune diseases of the CNS. On the basis of observations that i.n. infections with GAS in mice induces a robust Th17 response in nasal-associated lymphoid tissue that is replicated in naturally exposed human tonsils, Thamotharampillai Dileepan, Erica Smith, and colleagues investigated the role of CD4+ T cells in GAS-linked CNS autoimmu-nity. They found that multiple i.n. GAS challenges in mice promoted the migration to and persistence of GAS-specific Th17 cells in the brain through the cribriform plate and along olfactory sensory axons, leading to blood-brain barrier (BBB) breakdown (see the accompanying image). The loss of BBB integrity allowed additional T cell infiltration, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins. These data provide insights into the immunopathology underlying GAS-associated neurological complications.

Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cellsThamotharampillai Dileepan, Erica D. Smith, Daniel Knowland, Martin Hsu, Maryann Platt, Peter Bittner-Eddy, Brenda Cohen, Peter Southern, Elizabeth Latimer, Earl Harley, Dritan Agalliu, and P. Patrick Cleary http://jci.me/80792

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Research | Editor’s picks

Protecting positively selected B cell clones from apoptosis

Peer pressure: antigen-experienced T cells promote naive T cell differentiationthe ex vivo expansion and reinfusion of antigen-specific t cells is a promising therapy for patients with advanced cancer, but questions remain about the optimal source of the T cells used for therapeutic transfer. Christopher Klebanoff and colleagues found that antigen-experienced T cell subsets promote differentiation of naive T cells during ex vivo priming. The interaction of experienced and naive cells resulted in the loss of less-differentiated T cells and impaired the persistence and efficacy of therapeuti-cally transferred cells. Mechanistic investigations revealed that a nonapoptotic Fas/Akt signaling pathway mediated differentiation. Moreover, Fas signaling blockade prevented differentiation of naive cells and preserved antitumor efficacy. These results demonstrate that T cell subsets synchronize their differentiation state in a manner similar to that of the quorum-like behavior in unicellular organisms. In the accompanying Commentary, Yang Xu and Gianpietro Dotti discuss how strategies to disrupt differentiation could potentially enhance the effectiveness of T cell–based immunotherapies.

Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapyChristopher A. Klebanoff, Christopher D. Scott, Anthony J. Leonardi, Tori N. Yamamoto, Anthony C. Cruz, Claudia Ouyang, Madhu Ramaswamy, Rahul Roychoudhuri, Yun Ji, Robert L. Eil, Madhusudhanan Sukumar, Joseph G. Crompton, Douglas C. Palmer, Zachary A. Borman, David Clever, Stacy K. Thomas, Shashankkumar Patel, Zhiya Yu, Pawel Muranski, Hui Liu, Ena Wang, Francesco M. Marincola, Alena Gros, Luca Gattinoni, Steven A. Rosenberg, Richard M. Siegel, and Nicholas P. Restifo http://jci.me/81217

Related CommentarySelection bias: maintaining less-differentiated T cells for adoptive immunotherapyYang Xu and Gianpietro Dotti http://jci.me/85631

B cell antibody affinity for antigen is increased through an iterative process known as affinity maturation in which B cells cycle between somatic hypermutation and proliferation in the germinal center (GC) dark zone (DZ), which allows the acquisition of mutations that enhance antigen affinity, and clonal selection in the GC light zone (LZ). miR-155 is known to be required for efficient affinity maturation and the maintenance of GCs, but the underlying molecular mechanisms are unclear. Rinako Nakagawa and colleagues found that miR-155 is highly expressed in positively selected c-MYC+ LZ B cells. Mechanistically, miR-155 inhibits Jarid2 to prevent apoptosis of positively selected B cells. In the accompanying Commentary, Yee Ling Wu and Cristina Rada discuss how these

data demonstrate a functional link between c-MYC and miR-155 that supports the expansion of positively selected B cells during affinity maturation.

MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosisRinako Nakagawa, Rebecca Leyland, Michael Meyer-Hermann, Dong Lu, Martin Turner, Giuseppina Arbore, Tri Giang Phan, Robert Brink, and Elena Vigorito http://jci.me/82914

Related CommentaryMolecular fine-tuning of affinity maturation in germinal centersYee Ling Wu and Cristina Rada http://jci.me/85627

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Research | Editor’s picks

oncology

CD73 deficiency reduces epithelial integrity in endometrial cancer

NK cells mediate antitumor effects of a heparan sulfate mimeticheparanase mediates degradation of the extracellular matrix (ECM) and cleavage and release of heparan sulfate–bound (HS-bound) angiogenic factors to promote tumor invasion, metastasis, and angiogenesis. The HS mimetic PG545 is currently being investigated for the treatment of patients with advanced cancer, but the mechanisms underlying PG545’s antitumor effects are not completely defined. Using murine lymphoma models, researchers led by Yiping Yang demonstrate that PG545’s antitumor effects require NK cell activation. Mechanistic investigations revealed that PG545 indirectly activates TLR9 by promoting the accumulation of the TLR9 ligand CpG in DC lysosomes (see the accompanying image). The increased lysosomal CpG enhances DC production of IL-12, a proinflammatory cytokine that activates NK cells. These data identify NK cell–dependent mechanisms underlying the antitumor effects of an HS mimetic.

CD73 is a cell-surface protein that generates extracellular adenosine. Adenosine is generally thought to promote cancer through its immunosuppressive actions, but Jessica Bowser and colleagues found that CD73 is markedly downregulated in poorly differentiated and advanced-stage endometrial cancers. In endometrial epithelial cells, CD73 localized to membrane areas of cell-cell contacts and filopodia, and CD73 deficiency increased paracellular permeability under hypoxic conditions (see the accompa-nying image). CD73-generated adenosine activated the adenosine A1 receptor to induce actin polymerization through a pathway involving the Rho GTPase family member CDC42, N-WASP, and the ARP2/3 complex, thereby maintaining cell-cell adhesion and epithelial barrier integrity. Inhibition or loss of CD73 attenuated actin polymerization, reducing cellular adhesion and promoting migration and invasion. These data identify a mechanism by which loss of CD73 promotes cancer progression.

Loss of CD73-mediated actin polymerization promotes endometrial tumor progressionJessica L. Bowser, Michael R. Blackburn, Gregory L. Shipley, Jose G. Molina, Kenneth Dunner Jr., and Russell R. Broaddus http://jci.me/79380

Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activationTodd V. Brennan, Liwen Lin, Joshua D. Brandstadter, Victoria R. Rendell, Keith Dredge, Xiaopei Huang, and Yiping Yang http://jci.me/76566

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Research | Editor’s picks

neuroscience

Blood-brain barrier LRP1 deficiency impairs amyloid-β clearance

The PML-RARA fusion gene requires DNMT3A to initiate leukemiaMutations in the DnA methyl trans-ferase 3A gene (DNMT3A) occur in approximately 20% of patients with acute myeloid leukemia (AML) but almost never co-occur with chromosomal translocations that encode AML-initiating fusion genes. Christopher Cole and colleagues tested the hypothesis that these mutations may be mutually exclusive, because the fusion genes require DNMT3A for their activity. By transducing WT or DNMT3A-deficient BM cells with MLL-AF9–, AML-ETO–, or PML-RARA–expressing retroviruses, they demonstrated that DNMT3A is required for the aberrant self-renewal driven by PML-RARA, but not by the other fusion genes. Additionally, they showed that the DNA methyltransferase activity of DNMT3A is required for restoration of PML-RARA functions. PML-RARA–expressing BM cells had a competi-tive transplantation advantage over WT BM cells; however, without DNMT3A, the PML-RARA–expressing cells lost their advantage and were unable to initiate leukemia.

PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemiaChristopher B. Cole, Angela M. Verdoni, Shamika Ketkar, Elizabeth R. Leight, David A. Russler-Germain, Tamara L. Lamprecht, Ryan T. Demeter, Vincent Magrini, and Timothy J. Ley http://jci.me/82897

the low-density lipoprotein receptor–related protein-1 (lRP1) decreases with age and has been hypothesized to contribute to decreased amyloid-β (Aβ) clearance, leading to Alzheimer’s disease (AD). To test this hypothesis, Steffen Storck and colleagues engineered mice with selective knockout of Lrp1 in the brain endothelium (Slco1c1-CreERT2 mice). They found that brain endothelium–specific loss of Lrp1 markedly reduced brain efflux of injected Aβ peptide. Moreover, brain endothelium–specific deletion of Lrp1 in the murine AD model 5xFAD reduced plasma Aβ and increased soluble brain Aβ (see the accompanying image), which was accompanied by deficits in spatial learning and memory. These results indicate that impaired LRP1-mediated Aβ clearance contributes to AD.

Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrierSteffen E. Storck, Sabrina Meister, Julius Nahrath, Julius N. Meißner, Nils Schubert, Alessandro Di Spiezio, Sandra Baches, Roosmarijn E. Vandenbroucke, Yvonne Bouter, Ingrid Prikulis, Carsten Korth, Sascha Weggen, Axel Heimann, Markus Schwaninger, Thomas A. Bayer, and Claus U. Pietrzik http://jci.me/81108

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Research | Editor’s picks

metabolism

Serum amyloid A decreases HDL antiinflammatory effectshDl from healthy humans and mice attenuates adipocyte inflammation, but HDL from obese humans or inflamed mice does not. Chang Yeop Han and colleagues investigated whether the ability of HDL to inhibit inflammation is altered by serum amyloid A (SAA), which is increased in plasma during acute and chronic inflammation and is carried by HDL. They found that HDL from inflamed mice could not inhibit inflammation, stimulate cholesterol efflux, or suppress ROS generation in adipocytes. Notably, SAA enrichment completely abrogated the antiinflammatory effects of HDL, while knockdown of SAA in inflamed mice partially restored HDL antiinflammatory activity. SAA promoted the colocaliza-tion of HDL with the adipocyte cell surface through interactions with extracellular proteoglycans, potentially preventing HDL from accessing the plasma membrane to promote cholesterol efflux.

Serum amyloid A impairs the antiinflammatory properties of HDLChang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O’Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. de Beer, Frederick C. de Beer, William R. Osborne, Keith B. Elkon, and Alan Chait http://jci.me/83475

Gq/11α mediates melanocortin 4 receptor regulation of food intake

Melanocortin 4 receptors (MC4Rs) are GPCRs that regulate food intake, energy expenditure, insulin sensitivity, and linear growth. Outside of the paraventricu-lar nucleus of the hypothalamus (PVN), MC4R effects on energy expenditure and glucose metabolism appear to be mediated by Gsα; however, it is unclear which G proteins mediate MC4R-induced decreases in food intake and growth within the PVN. In this issue, Yong-Qi Li and colleagues showed that intra-PVN effects of MC4R are mediated by Gq/11α. PVN-specific knockout of Gq/11α in mice caused severe hyperphagic obesity (see the accompanying image), increased linear growth, and

inactivation of the hypothalamic-pituitary-adrenal axis but did not alter energy expenditure or glucose metabolism. PVN-specific delivery of MC4R agonists inhibited food intake in WT mice, but this effect was lost in animals with PVN-specific deletion of Gq/11α. These results suggest that appetite regulation could be selectively targeted with Gq/11α-biased MC4R agonists.

Gq/11α and Gsα mediate distinct physiological responses to central melanocortinsYong-Qi Li, Yogendra Shrestha, Mritunjay Pandey, Min Chen, Ahmed Kablan, Oksana Gavrilova, Stefan Offermanns, and Lee S. Weinstein http://jci.me/76348

Loss of the transcription factor E2F1 protects against hepatic steatosisin this issue, Pierre-Damien Denechaud and colleagues demonstrate that mice with liver-specific deletion of the transcription factor E2f1 exhibited impaired hepatic glycolysis and de novo lipogenesis. E2F1 expression and activity increased in response to feeding and insulin stimulation, leading to increased expression of genes mediating lipogenesis. Promoter analysis showed that E2F1 directly mediates the expression of acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, Srebp1c, and carbohydrate-responsive element–binding protein. In murine models of diabetes and obesity, E2F1 deficiency prevented the development of hepatic steatosis (see the accompanying image). Finally, E2F1 expression was increased in liver biopsies from obese, glucose-intolerant patients compared with that observed in lean subjects, indicating that E2F1 contributes to the development of hepatic steatosis.

E2F1 mediates sustained lipogenesis and contributes to hepatic steatosisPierre-Damien Denechaud, Isabel C. Lopez-Mejia, Albert Giralt, Qiuwen Lai, Emilie Blanchet, Brigitte Delacuisine, Brandon N. Nicolay, Nicholas J. Dyson, Caroline Bonner, François Pattou, Jean-Sébastien Annicotte, and Lluis Fajas http://jci.me/81542

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Features

conversations with giants in medicine

James AllisonJames Allison of the MD Anderson Cancer Center has made key discoveries on the regulation of T cell activation and modulation, including identification and characterization of the T cell antigen receptor and the T cell coreceptors CD28 and cytotoxic T lymphocyte antigen-4 (CTLA-4). He was awarded the 2015 Lasker~DeBakey Clinical Medical Research Award in honor of his discovery and subsequent

development of CTLA-4–targeted monoclonal antibody therapy to unleash the immune response to cancer. In an interview with JCI Editor at Large Ushma Neill, Allison discusses his decision to pursue a PhD instead of an MD and his early experiences in applying biochemical techniques to immunological questions. Additionally, Allison talks about the process of moving anti–CTLA-4 therapy into the clinic. http://jci.me/84088

reviews

Delineating the mechanisms that drive insulin resistanceinsulin resistance is a common feature of obesity, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and atherosclerosis. As these conditions have become increasingly prevalent, much effort has been invested in delineating the mechanisms that drive insulin resistance. Varman Samuel and Gerald Shulman review the role of insulin and nutrients in nutrient storage and examine the defects in these processes that give rise to insulin resistance, focusing on tissue-specific alterations in liver, skeletal muscle, and white adipose tissue. The caloric imbalance that characterizes the modern environment results in ectopic lipid accumulation in the skeletal muscle and liver that impairs insulin action in these tissues. Additionally, adipocyte dysfunction promotes inflammation and immune infiltration that increases lipolysis, resulting in further dysregulation (see the accompanying image). Therapeutic interventions targeting dysregulated metabolic pathways could potentially reverse insulin resistance and associated comorbidities.

The pathogenesis of insulin resistance: integrating signaling pathways and substrate fluxVarman T. Samuel and Gerald I. Shulman http://jci.me/77812

Sepsis-induced immune alterations and impaired long-term recoverysepsis is a constellation of symptoms resulting from a systemic inflammatory response to infection that includes fever, leukocytosis or leukopenia, hypotension, organ failure, and death. Despite advances in our understanding of the underlying immune pathology, there are currently no FDA-approved therapies for sepsis. Improve-ments in clinical treatment protocols have increased the number of patients that survive the initial stages of the disease, but these patients are still at a drastically increased risk for sepsis-associated mortality in the long term, after the patients have “recovered.” Matthew Delano and Peter Ward detail the sepsis-induced alterations in innate and adaptive immune responses that are involved in impaired sepsis recovery and survival. Additionally, they highlight the clinical implications and potential therapeutic interventions that could reverse these immune derangements to improve post-sepsis mortality.

Sepsis-induced immune dysfunction: can immune therapies reduce mortality?Matthew J. Delano and Peter A. Ward http://jci.me/82224

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