Editor's choice: featured articles (free access)
Articles published from 2015
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Special Issue: Cancer Immunology—Immunopathology
By Yutaka Kawakami
The immune system developed to respond against foreign materials invading the body and has a basic characteristic of not attacking self-cells. Unfortunately, potentially tumorigenic self-derived cells arise all the time and there has been much research on the pathological features of cancer tissues and the characteristics of the immune responses that are triggered or can be induced to prevent or eliminate tumors. Recent research has demonstrated the role of T cells, NK cells and other innate immune cells, as well as immune-evasion mechanisms used by tumor cells. The immune status in cancer appears to be defined by cancer cell characteristics, host immune-reactivity and environmental factors. Therefore, further understanding of human cancer immunopathology, particularly mechanisms of individual differences of immune-status, is important to improve current cancer immunotherapies possibly through the identification of biomarkers for personalized therapy. This is the second part of our Special Issue and comprises five review articles about the immunopathology of cancers.
Special Issue: Cancer Immunology—Immunotherapy
By Yutaka Kawakami
The ultimate aim of cancer research is to provide a platform that enables novel therapeutic intervention in cancer and one amazing aspect of the immune system is that we can not only observe it but also manipulate it, utilizing its mechanisms of action for vaccines and in therapeutic antibodies and lymphocytes. And after so many years of intensive research, very recently immunotherapy has begun to provide breakthrough treatments in oncology; this is especially the case, as mentioned in many of the articles in this Special Issue, with antibody-mediated immune-checkpoint inhibition and with engineered T cells. Arguably, cancer immunology has gone from bedside to bench and has returned, armed with better knowledge and effective therapeutics, to offer new hope against the diseases that affect so many of us. This is the first part of our Special Issue and comprises six review articles about the immunotherapy of cancers.
Functional development of CD4+ memory T cells features distinct, definable steps
By Tomohiro Kaji, Atsushi Hijikata, Akiko Ishige, Toshimori Kitami, Takashi Watanabe, Osamu Ohara, Noriyuki Yanaka, Mariko Okada, Michiko Shimoda, Masaru Taniguchi, and Toshitada Takemori
Using a wide variety of functional and phenotypic markers and analyzing genetic signatures, Kaji et al. track the development of CD4+ memory T cells (Tmem) that support the terminal differentiation of memory B cells much better than naive T cells do. Development of Tmem and follicular helper T cells (Tfh) requires Bcl6; however, Tmem show some distinct (but some similar) gene-expression patterns and Tmem can survive and persist in the absence of Tfh cells, germinal centers (GCs) and GC B cells. Cognate B cells are, however, required for functional development of Tmem, which releases the latter from a ‘paused’ state in terms of gene expression. The authors propose and detail a stepwise model for the development of Tmem, in which different stages feature different gene-expression profiles and result from interactions with different antigen-presenting cell types; some features are shared with Tfh (see the figure). Gdpd3 is, furthermore, identified as a potential marker for Tmem.
Guanosine and its modified derivatives are endogenous ligands for TLR7
By Takuma Shibata, Umeharu Ohto, Shosaku Nomura, Kayoko Kibata, Yuji Motoi, Yan Zhang, Yusuke Murakami, Ryutaro Fukui, Tatsushi Ishimoto, Shigetoshi Sano, Tomoki Ito, Toshiyuki Shimizu, and Kensuke Miyake
Human TLR7 and TLR8 are endosomal receptors for single-stranded RNA and are therefore crucial for immune responses against viruses. Recently, structural analyses have revealed TLR8 interaction with uridine and oligoribonucleotides (ORN). In this article, Shibata et al. show that uridine (and some uridine analogs) and a broad range of ORN synergistically activate human TLR8 expressed in human macrophages. In contrast, human and mouse TLR7 sense guanosine and some of its analogs with ORN. Macrophages and dendritic cells actually produce cytokines in vitro in response to guanosine and its derivatives with ORN. The authors discuss how TLR7 and TLR8 respond to nucleosides and ORN during infection, inflammation, autoimmunity and stress responses.
Introduction: Autoimmunity Special Issue
By Kazuhiko Yamamoto
There are about 80 recognized autoimmune diseases, which affect roughly 5% of the population. Despite extensive and very long-established knowledge of the features and pathogenesis of these diseases, they have in general proved difficult to ameliorate. Key features of autoimmune diseases are the wide variety of organs/systems targeted, the complexity of immune system components involved (innate, humoral and cellular) and the interplay of complex genetic and environmental elements. Thus, as is common with ‘experiments of nature’, they offer insights but shroud them in complexity. In this Special Issue, our first three Review articles discuss basic aspects of the immune response in autoimmunity, whereas the next two Reviews discuss therapeutic approaches that can target the disease. Finally, we include a research article that uses a model of autoimmunity to explore one potentially important mechanism whereby autoimmunity is just part of a complex interaction between the immune system and general metabolism.
The TCR signal strength influences stress responses in naive T cells
By Daisuke Kamimura, Yasunobu Arima, Mineko Tsuruoka, Jing-jing Jiang, Hidenori Bando, Jie Meng, Lavannya Sabharwal, Andrea Stofkova, Naoki Nishikawa, Kotaro Higuchi, Hideki Ogura, Toru Atsumi, and Masaaki Murakami
Signals induced by various forms of cellular stress converge on integrated stress responses (ISR), which involves EIF-2α phosphorylation, reduced protein synthesis, up-regulated stress-related genes and increased apoptosis. KDEL receptors transport chaperones in the Golgi complex and the ER but also function in ER stress responses. In naive T cells, KDELR dysfunction inhibits PP1 (a phosphatase that inactivates EIF-2α), exaggerates ISR and increases apoptosis. Using a model in which naive T cells are susceptible to apoptosis because of functional KDELR deficiency, Kamimura et al. show that surviving naive T cells have higher affinity/avidity for self antigens. Ovalbumin-derived altered-peptide ligands with varying TCR affinity also show that TCR signal strength is linked to ISR: high affinity TCR–antigen interactions overcome the exaggerated ISR associated with KDELR dysfunction; however, interactions that are below a cut-off threshold leave naive T cells vulnerable to reduced survival and proliferation. The authors discuss the mechanisms involved in linking TCR signaling to ISR.
High blood cmTreg numbers predict acute rejection of liver transplants
By Francisco Boix-Giner, Olga Millan, David San Segundo, Pedro Muñoz-Cacho, Esther Mancebo, Santiago Llorente, Lourdes Rafael-Valdivia, Antoni Rimola, Emilio Fábrega, Anna Mrowiec, Luis Allende, Alfredo Minguela, Jose M. Bolarín, Estela Paz-Artal, Marcos López-Hoyos, Mercé Brunet, and Manuel Muro
Although allogeneic livers are more-readily accepted than other organs, acute rejection and re-infection with hepatitis C virus (HCV) remain as major causes of loss of transplant function. Regulatory T cells (Tregs) are thought to suppress the recipient responses not only to the allograft but also to HCV. In this prospective, multi-center study, Boix-Giner et al. measure, for up to a year, numbers of the central memory Treg (cmTreg; CD4–CD25highCD45RO+CD62L+) subset in the blood of 64 of liver transplant recipients. The 16 patients who were re-infected with HCV actually had low levels of cmTregs compared with patients who were not re-infected. Among the 15 patients who developed acute rejection, levels of blood cmTregs were in fact increased in the first month post-transplantation compared with patients who did not have acute rejection. Using this straightforward protocol, the authors formulate a model that monitors and predicts the risk of developing acute rejection in the month after allogeneic liver transplantation.
Introduction: Innate Lymphoid Cells Special Issue
By Shigeo Koyasu
Recent progress in characterizing innate lymphoid cells (ILCs) has been remarkably fast; pioneering studies of relatively rare cells with novel properties isolated from different sites have been drawn together quickly and, despite the complexity of the picture, patterns have emerged in the context of known features of adaptive immunity. In this Special Issue of review articles, our authors provide a comprehensive update on the phenotype, functions and inter-relationships of ILC subsets.
SHM generates different antibody repertoires in plasmablasts compared with plasma cells
By Yasuyuki Tashiro, Akikazu Murakami, Ryo Goizuka, Takeyuki Shimizu, Hidehiro Kishimoto, and Takachika Azuma
In C57BL/6 mice, antibodies to the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) utilize canonical genes and are therefore relatively homogeneous, allowing study of somatic hypermutation (SHM)-induced increases in BCR/antibody affinity. Here, Tashiro et al. (p. 609) use a novel method to isolate plasma cells and compare NP-reactive antibodies from them with those from plasmablasts and from memory B cells. In the first week of the primary response, >90% of antibody-secreting cells (ASCs) are plasmablasts and their antibodies are ‘germline’ V186.2+Tyr95+. After the first week, ASCs (again mostly plasmablasts) increase antibody affinity by substituting Leu33 for Trp33 (V186.2+Tyr95+Leu33+); at this stage, V186.2+Tyr95+ and even-higher-affinity V186.2+Gly95+ memory cells are also generated in germinal centers. Secondary immunization does not alter the memory B cell repertoire but induces a large number of plasma cells that secrete V186.2+Gly95+ antibodies; plasmablasts do not secrete these antibodies and therefore have a different repertoire. The authors discuss the importance of affinity maturation in plasma cell differentiation.
Retinoic acid modulates the functions of IL-4 in alternatively activated DCs
By Lucy H. Jones, Peter C. Cook, Alasdair C. Ivens, Graham, D. Thomas, Alexander T. Phythian-Adams, Judith E. Allen and Andrew S. MacDonald
IL-4 drives the differentiation not only of Th2 CD4+ cells but also of ‘alternatively’ activated dendritic cells (DCs), which express the marker resistin-like molecule α (RELMα; encoded by Retnla). In recruited peritoneal macrophages, IL-4 induces aldehyde dehydrogenase 1A2 (encoded by Aldh1a2), which catalyzes the formation of retinoic acid (RA)—the transcriptionally active metabolite of vitamin A. In their Short Communication, Jones et al. (p. 589) show that over 100 genes are upregulated in bone-marrow-derived DCs responding to IL-4 in vitro; Aldh1a2 is among the most strongly upregulated and the active enzyme is expressed. In vivo, IL-4 upregulates Aldh1a2, (and active enzyme) and Retnla in peritoneal DCs but not in tissue-resident macrophages. RA by itself does not induce RELMα, but it enhances IL-4-mediated RELMα induction. In DC–T co-culture with exogenous IL-4, RA decreases Il4 transcription and IL-13 secretion but increases IL-10 secretion. RA therefore interacts in a complex way with IL-4 to influence Th2 polarization by alternatively activated DCs.
Introduction: Regulatory B Cell Special Issue—making all the pieces fit
By Thomas F. Tedder
Specific and functionally important B-cell subsets with negative regulatory properties have been recently identified that contribute to immunological tolerance by down-modulating immune responses under homeostatic, as well as inflammatory and pathogenic, conditions. This Special Issue focuses both on regulatory B-cell subsets that suppress symptoms in a wide range of human diseases and experimental models, and on other B-cell subsets that augment acute and chronic inflammation.
PIKfyve modulates endosomes in TLR9-mediated induction of type I IFNs
By Kachiko Hayashi, Miwa Sasai, and Akiko Iwasaki
Although TLR-family molecules have limited structural variability, their differential expression, variable cellular localization and complex signal transduction allow a range of responses. For example, dendritic cells (DCs) use endosomal TLR9 to recognize unmethylated CpG in viral DNA, then can induce either pro-inflammatory cytokines (via the ‘NF-κB endosome’) or type I IFNs (via the ‘IRF7 endosome’, which requires AP-3 for its development). PIKfyve generates PI(3,5)P2, which is crucial for endosome maturation and functions. Using a specific inhibitor of PIKfyve in plasmacytoid and conventional DCs, Hayashi et al. (p. 435) show blocked CpG–TLR9-mediated induction of type I IFNs, but not IL-12p40; TLR3/4/7-mediated cytokine induction is not affected. In RAW267.4 macrophages, trafficking of TLR9 and CpG to NF-κB endosomes is not affected by PIKfyve inhibition but TLR9 and CpG are excluded from IRF7 endosomes. CpG-induced recruitment of AP-3 to endosomes is impaired after PIKfyve inhibition. The authors propose that PI(3,5)P2 promotes AP-3 recruitment to induce type I IFNs via the IRF7 endosome.
The Ahr and microRNA-212/132 regulate intestinal inflammation
By Ichino Chinen, et al.
The aryl hydrocarbon receptor (Ahr) is a transcription factor known to play a role in many immune responses, e.g. inflammatory bowel disease (IBD), and is known to induce expression of microRNA molecules including miR-212 and miR-132, whose genes are found in a cluster. Using the model of DSS-induced colitis in mice, Chinen et al. (p. 405), show elevated levels of miR-212 and miR-132 in lamina propria lymphocytes during inflammation. Deficiency of miR-212 and mi-R132 leads to resistance to colitis, lower Th17 responses and increased IL-10-producing CD4+ cells; and miR-212, but not miR-132, reduces Tr1 levels via c-Maf. Ahr deficiency in intestinal epithelial cells exacerbates colitis; whereas Ahr deficiency in T cells attenuates colitis and suppresses lamina propria Th 17 cell infiltration. T cell Ahr deficiency causes lower miR-212/132 expression. The Ahr therefore has varying effects in different cell populations but the T cell Ahr–miR-212/132 axis can promote IBD by enhancing Th17 responses while suppressing sing IL-10.
The zinc-finger antiviral protein prevents replication of Sindbis virus
By Tatsuya Kozaki, Michihiro Takahama, Takuma Misawa, Yoshiharu Matsuura, Shizuo Akira, and Tatsuya Saitoh
Sindbis virus (SINV) is a single-stranded RNA virus that is transmitted by mosquitos and can cause severe disease in humans. Type I interferons (type I IFNs) and the genes they induce are crucial for responses to viruses, including SINV, but the effector molecules and mechanisms are not completely characterized. Zinc-finger antiviral protein (ZAP) is an interferon-induced gene that belongs to the structurally and functionally heterogeneous ‘zinc-finger protein’ family and targets many diverse viruses, including HIV and Ebola. Initially using mouse embryonic fibroblasts (MEFs), Kozaki et al. (p.357) show that the loss of ZAP enhances SINV replication in vitro despite not affecting type I IFN production; conversely, ectopic expression of ZAP suppresses virus replication in MEFs lacking type I IFNs and interferon-inducible genes. ZAP-deficient mice are highly susceptible to SINV in vivo despite producing type I IFNs. The authors conclude that ZAP is the crucial interferon-inducible effector molecule that senses, binds and destabilizes SINV.
PILRα ameliorates the symptoms and severity of colitis
By Kazuki Kishida, Masako Kohyama, Yosuke Kurashima, Yuta Kogure, Jing Wang, Kouyuki Hirayasu, Tadahiro Suenaga, Hiroshi Kiyono, Jun Kunisawa and Hisashi Arase
Inflammatory bowel diseases, for example ulcerative colitis (UC), feature chronic infiltration by immune cells, in particular neutrophils; one model of UC is induced by DSS. PILRα is a well-characterized receptor that transmits inhibitory signals and is mainly expressed on myeloid cells. Using PILRα-deficient (Pilra–/–) mice, Kishida et al. (p. 307) examine the effects on colitis. The disease symptoms, severity and mortality rates after DSS administration are worse in Pilra–/– mice compared with wild-type (WT). Pilra–/– mice have severe mucosal damage in the colon, with inflammatory cell infiltration, featuring higher numbers of neutrophils and macrophages but not monocytes, dendritic cells, T cells or mast cells. In WT mice, most neutrophils, and about 15% of macrophages, express PILRα. Blockade of CXCR2 using an antagonist reduces the severity of colitis in PILRα-deficient mice without affecting neutrophil numbers. PILRα is therefore important in reducing the severity of colitis by influencing neutrophil and macrophage recruitment and functions.
NKT cells and IL-4 mediate protective effects of vitamin D against EAE
By Amanda Waddell, Jun Zhao and Margherita T. Cantorna
The active form of vitamin D3—1,25-dihydroxyvitamin D3 (1,25D3)— is known to prevent autoimmune responses such as EAE (a model of multiple sclerosis induced by e.g. MOG); it also regulates NKT cells. In MOG-induced EAE, Waddell et al. (p.237 ) feed 1,25D3 to wild-type mice, mice lacking all NKT cells (CD1d–/–), lacking ‘invariant’ NKT cells (Jα18–/–) or lacking IL-4 (IL-4M–/–). Wild-type mice are protected from EAE by 1,25D3 and produce less IL-17 and IFN-γ; CD1d–/– mice were less well protected (as were Jα18–/– mice) and there was no reduction in IL-17 and IFN-γ. IL-4–/– mice are not protected by 1,25D3 or by α-GalCer (which activates NKT cells and is known to protect against EAE). In wild-type splenocytes in vitro, 1,25D3 reduces α-GalCer-induced IL-17, but increases IL-4 production. The authors conclude that NKT cells are important in 1,25D3-mediated protection and that IL-4 is clearly involved in the process.
APCs use CCR8 to remain in the skin and suppress allergic contact dermatitis
By Rikio Yabe, Kenji Shimizu, Soichiro Shimizu, Satoe Azechi, Byung-Il Choi, Katsuko Sudo, Sachiko Kubo, Susumu Nakae, Harumichi Ishigame, Shigeru Kakuta and Yoichiro Iwakura
Contact hypersensitivity (CHS) is induced using the hapten 2,4-dinitrofluorobenzene in a model of allergic contact dermatitis—a common form of delayed-type hypersensitivity in humans. In CHS, hapten activates dendritic cells (DCs), which migrate to draining lymph nodes (LNs) using CCR7–CCL19/CCL21, where they sensitize T cells; upon re-exposure, the hapten activates memory and effector T cells to elicit inflammation. Here, Yabe et al. (p. 169) report upregulated Langerhans cell (LC) CCR8 and keratinocyte CCL8 in CHS. Ccr8–/– mice are more susceptible than wild-type (WT) mice to CHS, with expanded Th1/Th17/Tc1 LN populations; and T cells from hapten-sensitized Ccr8–/– mice show enhanced hapten-induced proliferation. In WT mice, T cells transferred from draining LNs of Ccr8–/– mice elicit enhanced CHS responses. In Ccr8–/– mice, LCs, dermal DCs and inflammatory DCs migrate to, and accumulate in, draining LNs after sensitization. The authors conclude that CCR8 retains antigen-presenting cells (APCs) in the skin, reducing migration to LNs and decreasing CHS.
IRF-1 suppresses Th2 responses in Listeria infection in vivo
By Saho Maruyama, Makoto Kanoh, Akira Matsumoto, Makoto Kuwahara, Masakatsu Yamashita and Yoshihiro Asano
A paradigm of Th1 responses is protection against intracellular bacteria such as Listeria monocytogenes, which survives and multiplies in antigen-presenting cells (APCs). The transcription factor interferon regulatory factor-1 (IRF-1) is involved in Th1 cell induction via transcription of the IL-12p40 gene in APCs. Using mice with disrupted genes for IRF-1 or IL-12p40, Maruyama et al. (p. 143) show that, although IRF-1 is not essential for Th1-associated T-cell IFN-γ production following in vivo Listeria infection, IL-12p40 is required; whereas inhibition of Th2-associated IL-4 production requires IRF-1 but not IL-12p40. IL-4, but not IFN-γ, production can be inhibited by supernatant from Listeria-infected APCs during culture of spleen cells in vitro. This activity is due to IL-1α and IL-1β, via the T-cell IL-1R. IL-1R stabilizes IRF-1 and increases its nuclear translocation, where it binds the 3′untranslated region of Il4 and decreases transcription. The authors conclude that IRF-1 not only induces Th1 responses but also suppresses Th2 responses.
A new anti-LAP antibody that enhances inflammation in vivo
By Andre P. da Cunha, Henry Y. Wu, Rafael M. Rezende, Tyler Vandeventer and Howard L. Weiner
Cell surface transforming growth factor-β (TGF-β) is crucial for Treg cell-mediated immunosuppression. Latency-associated peptide (LAP) forms a complex with TGF-β, and LAP+ Treg cells are induced in anti-CD3-stimulated oral tolerance to MOG peptides that otherwise induce experimental autoimmune encephalomyelitis (EAE) (a model of multiple sclerosis). Here, da Cunha et al.(p. 73) report the effects of their mAb against mouse LAP in vivo. In naive mice, anti-LAP decreases the percentage of LAP+ cells among CD4+ T cells and among Foxp3+ Treg cells in spleen and lymph nodes without affecting the percentage of CD4+Foxp3+ Treg cells. Treg cell suppressive activity is unaffected but anti-LAP-treated CD4+ T cells are pro-inflammatory (increased proliferation IL-2, IL-17 and IFN-γ) in vitro. In vivo, anti-LAP abrogates the protective effect of anti-CD3 on MOG-induced EAE; if MOG is given without pertussis toxin (or anti-CD3), anti-LAP worsens EAE, with increased Th1 and Th17 cell infiltration. The new reagent therefore reveals roles for CD4+LAP+ T cells in immunosuppression, inflammation and autoimmunity.
Introduction: Antibody-Targeted Therapy Special Issue
By Tadamitsu Kishimoto
Lymphocytes are the crucial orchestrators of the adaptive immune system because the enormous flexibility of antibody or TCR gene expression and modification in B or T lymphocyte populations allows adaptive selection of individual lymphocytes that express antibodies or TCRs that can recognize and tag almost any candidate molecule and potentially trigger a range of effector functions. In this Special Issue of review articles, our authors detail many of the current and future uses of antibodies in human diseases.
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