Nature Medicine. doi:10.1038/nm.1993

Authors: Tim A Weaver, Ali H Charafeddine, Avinash Agarwal, Alexandra P Turner, Maria Russell, Frank V Leopardi, Robert L Kampen, Linda Stempora, Mingqing Song, Christian P Larsen & Allan D Kirk

Memory T cells promote allograft rejection particularly in co-stimulation blockade–based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (lymphocyte function–associated antigen-3–Ig; LFA -3–Ig) selectively eliminates memory T cells and, when combined with a co-stimulation blockade–based regimen using cytotoxic T lymphocyte antigen-4 (CTLA-4)-Ig, a CD80- and CD86-specific fusion protein, prevents renal allograft rejection and alloantibody formation in nonhuman primates. These results support the immediate translation of a regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids or pan–T cell depletion.

Nature Medicine. doi:10.1038/nm.1997

Authors: Henriette Kirchner, Jesus A Gutierrez, Patricia J Solenberg, Paul T Pfluger, Traci A Czyzyk, Jill A Willency, Annette Schürmann, Hans-Georg Joost, Ronald J Jandacek, John E Hale, Mark L Heiman & Matthias H Tschöp

Central nervous system nutrient sensing and afferent endocrine signaling have been established as parallel systems communicating metabolic status and energy availability in vertebrates. The only afferent endocrine signal known to require modification with a fatty acid side chain is the orexigenic hormone ghrelin. We find that the ghrelin O-acyl transferase (GOAT), which is essential for ghrelin acylation, is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates and links ingested lipids to energy expenditure and body fat mass. These data implicate the ghrelin-GOAT system as a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence as is commonly accepted.

Nature Medicine. doi:10.1038/nm.1983

Authors: Hayriye V Erkizan, Yali Kong, Melinda Merchant, Silke Schlottmann, Julie S Barber-Rotenberg, Linshan Yuan, Ogan D Abaan, Tsu-hang Chou, Sivanesan Dakshanamurthy, Milton L Brown, Aykut Üren & Jeffrey A Toretsky

Nature Medicine. doi:10.1038/nm.1979

Authors: Yi Tang, Xiangwei Wu, Weiqi Lei, Lijuan Pang, Chao Wan, Zhenqi Shi, Ling Zhao, Timothy R Nagy, Xinyu Peng, Junbo Hu, Xu Feng, Wim Van Hul, Mei Wan & Xu Cao

Nature Medicine. doi:10.1038/nm.1984

Authors: Eugene Y Chiang, Ganesh A Kolumam, Xin Yu, Michelle Francesco, Sinisa Ivelja, Ivan Peng, Peter Gribling, Jean Shu, Wyne P Lee, Canio J Refino, Mercedesz Balazs, Andres Paler-Martinez, Allen Nguyen, Judy Young, Kai H Barck, Richard A D Carano, Ron Ferrando, Lauri Diehl, Devavani Chatterjea & Jane L Grogan

Nature Medicine. doi:10.1038/nm.1987

Authors: Kim Midwood, Sandra Sacre, Anna M Piccinini, Julia Inglis, Annette Trebaul, Emma Chan, Stefan Drexler, Nidhi Sofat, Masahide Kashiwagi, Gertraud Orend, Fionula Brennan & Brian Foxwell

Nature Medicine. doi:10.1038/nm.1972

Authors: Nicolas Chomont, Mohamed El-Far, Petronela Ancuta, Lydie Trautmann, Francesco A Procopio, Bader Yassine-Diab, Geneviève Boucher, Mohamed-Rachid Boulassel, Georges Ghattas, Jason M Brenchley, Timothy W Schacker, Brenna J Hill, Daniel C Douek, Jean-Pierre Routy, Elias K Haddad & Rafick-Pierre Sékaly

Nature Medicine. doi:10.1038/nm.1970

Authors: Coreen M Beaumier, Levelle D Harris, Simoy Goldstein, Nichole R Klatt, Sonya Whitted, John McGinty, Cristian Apetrei, Ivona Pandrea, Vanessa M Hirsch & Jason M Brenchley

Nature Medicine. doi:10.1038/nm.1978

Authors: Tony Muchamuel, Michael Basler, Monette A Aujay, Erika Suzuki, Khalid W Kalim, Christoph Lauer, Catherine Sylvain, Eileen R Ring, Jamie Shields, Jing Jiang, Peter Shwonek, Francesco Parlati, Susan D Demo, Mark K Bennett, Christopher J Kirk & Marcus Groettrup

Nature Medicine. doi:10.1038/nm.1967

Authors: Philip R Johnson, Bruce C Schnepp, Jianchao Zhang, Mary J Connell, Sean M Greene, Eloisa Yuste, Ronald C Desrosiers & K Reed Clark

Nature Medicine. doi:10.1038/nm.1980

Authors: Ulf Schulze-Topphoff, Alexandre Prat, Timour Prozorovski, Volker Siffrin, Magdalena Paterka, Josephine Herz, Ivo Bendix, Igal Ifergan, Ines Schadock, Marcelo A Mori, Jack Van Horssen, Friederike Schröter, Alina Smorodchenko, May Htwe Han, Michael Bader, Lawrence Steinman, Orhan Aktas & Frauke Zipp

Previous proteomic and transcriptional analyses of multiple sclerosis lesions revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[D-Phe]des-Arg9-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-βNal7, Ile8]des-Arg9-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1−/−) C57BL/6 mice immunized with a myelin oligodendrocyte glycoprotein fragment, MOG35–55, showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow–chimeric mice reconstituted with Bdkrb1−/− T lymphocytes, which showed enhanced T helper type 17 (TH17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human TH17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.

Nature Medicine. doi:10.1038/nm.1961

Authors: Yorihiro Nishimura, Masayuki Shimojima, Yoshio Tano, Tatsuo Miyamura, Takaji Wakita & Hiroyuki Shimizu

Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), a common febrile disease occurring mainly in young children. Although clinical manifestations of HFMD are usually mild and self limiting, a severe EV71 outbreak can lead to a diverse array of neurological diseases. Identification of the specific cellular receptors is crucial for elucidating the mechanism of early virus-host interactions and the pathogenesis of enteroviruses. Here we identify human P-selectin glycoprotein ligand-1 (PSGL-1; CD162), a sialomucin membrane protein expressed on leukocytes that has a major role in early stages of inflammation, as a functional receptor for EV71 using an expression cloning method by panning. The N-terminal region of PSGL-1 binds specifically to EV71. Stable PSGL-1 expression allowed EV71 entry and replication, and development of cytopathic effects in nonsusceptible mouse L929 cells. Five out of eight EV71 strains bound soluble PSGL-1 and used intact PSGL-1 as the primary receptor for infection of Jurkat T cells. Three other EV71 strains did not use PSGL-1, suggesting the presence of strain-specific replication of EV71 in leukocytes. EV71 replicated in nonleukocyte cell lines in a PSGL-1–independent manner, indicating the presence of alternative receptor(s) for EV71. The identification of PSGL-1 as a receptor for EV71 sheds new light on a role for PSGL-1–positive leukocytes in cell tropism and pathogenesis during the course of HFMD and other EV71-mediated diseases.

Nature Medicine. doi:10.1038/nm.1992

Authors: Seiya Yamayoshi, Yasuko Yamashita, Jifen Li, Nobutaka Hanagata, Takashi Minowa, Taro Takemura & Satoshi Koike

Enterovirus 71 (EV71) belongs to human enterovirus species A of the genus Enterovirus within the family Picornaviridae. EV71, together with coxsackievirus A16 (CVA16), are most frequently associated with hand, foot and mouth disease (HFMD). Although HFMD is considered a mild exanthematous infection, infections involving EV71, but not CVA16, can progress to severe neurological disease, including fatal encephalitis, aseptic meningitis and acute flaccid paralysis. In recent years, epidemic and sporadic outbreaks of neurovirulent EV71 infections have been reported in Taiwan, Malaysia, Singapore, Japan and China. Here, we show that human scavenger receptor class B, member 2 (SCARB2, also known as lysosomal integral membrane protein II or CD36b like-2) is a receptor for EV71. EV71 binds soluble SCARB2 or cells expressing SCARB2, and the binding is inhibited by an antibody to SCARB2. Expression of human SCARB2 enables normally unsusceptible cell lines to support EV71 propagation and develop cytopathic effects. EV71 infection is hampered by the antibody to SCARB2 and soluble SCARB2. SCARB2 also supports the infection of the milder pathogen CVA16. The identification of SCARB2 as an EV71 and CVA16 receptor contributes to a better understanding of the pathogenicity of these viruses.

Nature Medicine. doi:10.1038/nm.1982

Authors: Luca Gattinoni, Xiao-Song Zhong, Douglas C Palmer, Yun Ji, Christian S Hinrichs, Zhiya Yu, Claudia Wrzesinski, Andrea Boni, Lydie Cassard, Lindsay M Garvin, Chrystal M Paulos, Pawel Muranski & Nicholas P Restifo

Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways. The Wnt–β-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt–β-catenin signaling by inhibitors of glycogen sythase kinase-3β or the Wnt protein family member Wnt3a arrested CD8+ T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44lowCD62LhighSca-1highCD122highBcl-2high self-renewing multipotent CD8+ memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8+ T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.

Nature Medicine. doi:10.1038/nm.1974

Authors: Ann J Hessell, Pascal Poignard, Meredith Hunter, Lars Hangartner, David M Tehrani, Wim K Bleeker, Paul W H I Parren, Preston A Marx & Dennis R Burton

Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required. This is a major potential hurdle for vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. We investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titers in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus–HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function–deficient variant of the neutralizing antibody was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody–treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.

Nature Medicine. doi:10.1038/nm.1976

Authors: Matthias Schweizerhof, Sebastian Stösser, Martina Kurejova, Christian Njoo, Vijayan Gangadharan, Nitin Agarwal, Martin Schmelz, Kiran Kumar Bali, Christoph W Michalski, Stefan Brugger, Anthony Dickenson, Donald A Simone & Rohini Kuner

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve–specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.