European Journal of Immunology (Eur J Immunol )

Publisher: European Federation of Immunological Societies, John Wiley and Sons

Description

The European Journal of Immunology is an international journal focusing on the various aspects of immunological research. One of the world's leading journals of immunology it reports on the latest breakthroughs in the area. The European Journal of Immunology is a well-respected high-impact publication with the best Executive Committee in the field. Top authors have submitted their best papers to the journal for many years therefore building a high quality immunology journal. An ever-increasing amount of papers is being published from top authors from all over the world. The European Journal of Immunology is committed to publishing excellence with a focus on originality topicality and speed of publication. Well balanced coverage of immunology! The European Journal of Immunology provides a monthly forum for top-quality papers on the various aspects of immunological research. Original papers and short communications report the progress being made in the following fields of immunology: immunobiology experimental/human immunology molecular immunology immunopathology immunogenetics clinical immunology The Executive Committee and the international Editorial Board ensure the publication of high quality papers and an international and broad subject coverage. Kurztext Diese Zeitschrift zählt zur Weltspitze der wissenschaftlichen Immunologie-Journale. In ihr erscheinen Originalbeiträge und Kurzmitteilungen aus einem außerordentlich weiten Themengebiet. Hierzu gehören Aspekte der molekularen Immunologie der Immunogenetik der Cytokine der Immunochemie sowie der zellulären und klinischen Immunologie. Es werden außerdem Beiträge zu neuen Entwicklungen experimenteller Methoden und Techniken veröffentlicht. Society Affiliation European Federation of Immunological Societies (EFIS) Readers Immunologists biochemists molecular biologists cell biologists

Impact factor 4.52

  • Hide impact factor history
     
    Impact factor
  • 5-year impact
    4.77
  • Cited half-life
    8.10
  • Immediacy index
    0.74
  • Eigenfactor
    0.06
  • Article influence
    1.98
  • Website
    European Journal of Immunology website
  • Other titles
    European journal of immunology (Online), European Journal of Immunology, EJI
  • ISSN
    1521-4141
  • OCLC
    41614778
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

John Wiley and Sons

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • See Wiley-Blackwell entry for articles after February 2007
    • On personal web site or secure external website at authors institution
    • Deposit in institutional repositories is not allowed
    • JASIST authors may deposit in an institutional repository
    • Non-commercial
    • Pre-print must be accompanied with set phrase (see individual journal copyright transfer agreements)
    • Published source must be acknowledged with set phrase (see individual journal copyright transfer agreements)
    • Publisher's version/PDF cannot be used
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'John Wiley and Sons' is an imprint of 'Wiley'
  • Classification
    ​ green

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: The organization of the thymus into distinct cortical and medullary regions enables it to control the step-wise migration and development of immature T-cell precursors. Such a process provides access to specialized cortical and medullary thymic epithelial cells at defined stages of maturation, ensuring the generation of self-tolerant and MHC-restricted conventional CD4+ and CD8+ αβ T cells. The migratory cues and stromal cell requirements that regulate the development of conventional αβ T cells have been well studied. However, the thymus also fosters the generation of several immunoregulatory T-cell populations that form key components of both innate and adaptive immune responses. These include Foxp3+ natural regulatory T cells, invariant γδ T cells, and CD1d-restricted invariant natural killer T cells (iNKT cells). While less is known about the intrathymic requirements of these non-conventional T cells, recent studies have highlighted the importance of the thymus medulla in their development. Here we review recent findings on the mechanisms controlling the intrathymic migration of distinct T-cell subsets, and relate this to knowledge of the microenvironmental requirements of these cells.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • Esam T. Abualrous, Susanne Fritzsche, Zeynep Hein, Mohammed S. Al‐Balushi, Peter Reinink, Louise H. Boyle, Ursula Wellbrock, Antony N. Antoniou, Sebastian Springer
    [Show abstract] [Hide abstract]
    ABSTRACT: The human major histocompatibility complex (MHC) class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis (AS), unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • Tamar Kapanadze, José Medina‐Echeverz, Jaba Gamrekelashvili, Jonathan M. Weiss, Robert H. Wiltrout, Veena Kapoor, Nga Hawk, Masaki Terabe, Jay A. Berzofsky, Michael P. Manns, Ena Wang, Francesco M. Marincola, Firouzeh Korangy, Tim F. Greten
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing mice. We studied hepatic MDSCs in two murine models of immune mediated hepatitis. Unexpectedly, treatment of tumor bearing mice with Concanavalin A or α-Galactosylceramide resulted in increased ALT and AST serum levels in comparison to tumor free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Concanavalin A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized pro-inflammatory gene signature after Concanavalin A treatment. An IFN-γ-dependent up regulation of CD40 on hepatic CD11b+Gr-1+ cells along with an up regulation of CD80, CD86, and CD1d after Concanavalin A treatment was observed. Concanavalin A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSCs as well as enhanced reactive oxygen species-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Concanavalin A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40−/− tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased reactive oxygen species production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as pro-inflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • Hou‐Pu Liu, Anthony T. Cao, Ting Feng, Qingjie Li, Wenbo Zhang, Suxia Yao, Sara M. Dann, Charles O. Elson, Yingzi Cong
    [Show abstract] [Hide abstract]
    ABSTRACT: Differentiated CD4+ T cells preserve plasticity under various conditions. However, the stability of Th1 cells is unclear, as is whether Th1 cells can convert into Th17 cells and thereby contribute to the generation of IFN-γ+IL-17+CD4+ T cells, the number of which correlates with severity of colitis. We investigated whether IFN-γ+Th1 cells can convert into Th17 cells under intestinal inflammation and the mechanisms involved. IFN-γThy1.1+ Th1 cells were generated by culturing naïve CD4+ T cells from IFN-γThy1.1 CBir1 TCR-Tg reporter mice, whose TCR is specific for an immunodominant microbiota antigen, CBir1 flagellin, under Th1 polarizing conditions. IFN-γThy1.1+ Th1 cells induced colitis in Rag−/− mice after adoptive transfer and converted into IL-17+Th17, but not Foxp3+Treg cells in the inflamed intestines. TGF-β and IL-6, but not IL-1β and IL-23, regulated Th1 conversion into Th17 cells. TGF-β induction of transcriptional factor Runx1 is crucial for the conversion, since silencing Runx1 by siRNA inhibited Th1 conversion into Th17 cells. Furthermore, TGF-β enhanced histone H3K9 acetylation but inhibited H3K9 trimethylation of Runx1- and RORγt-binding sites on il-17 or rorc genes in Th1 cells. We conclude that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which is possibly mediated by TGF-β induction of Runx1.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cell (DC) homeostasis is influenced by multiple factors, including the availability of GM-CSF and Flt3L, both of which exert positive effects on DC differentiation and survival. Interleukin 2 (IL-2) and regulatory T (Treg) cells have recently been proposed as negative regulators of DC numbers. It remains unclear whether their effects in immunosufficient mice are direct, or are mediated via activation of conventional T cells in response to deficiencies of IL-2 and/or Treg cells. Using a number of in vivo models, we have assessed the role of IL-2 and Treg-cell number on conventional splenic and lymph node DCs. We have found no evidence for a direct role of IL-2 or Treg cells in negatively regulating DC number. Our data indicate that the expansion of DCs in the absence of either IL-2 or Treg cells is an indirect effect secondary to the activation and proliferation of conventional T cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although it has been shown that human tumour-associated, HLA anchor residue-modified “heteroclitic” peptides may induce stronger immune responses than wild-type peptides in cancer vaccine trials, it has also been shown that some T cells primed with these heteroclitic peptides subsequently fail to recognise the natural, tumour-expressed peptide efficiently. This may provide a molecular reason for why clinical trials of these peptides have been thus far unsuccessful. In this issue of the European Journal of Immunology, Madura et al. [Eur. J. Immunol. 2015. 45: XXXX-XXXX] highlight a novel twist on T-cell receptor (TCR) recognition of HLA-peptide complexes. Tumour-associated peptides often lack canonical anchor residues, which can be substituted for the optimal residue to improve their antigenicity. T-cell cross-reactivity between the natural and modified (heteroclitic) peptides is essential for this approach to work and depends on whether the anchor residue substitution influences peptide conformation. The Melan-A/MART-126-35 peptide epitope is an example where T cells can make this distinction, with the natural peptide stimulating higher affinity CD8+ T cells than the heteroclitic peptide, despite the heteroclitic peptide's more stable association with HLA-A2. The molecular basis for peptide discrimination is identified through the structure of the TCR bound to the natural peptide; TCR engagement of the natural peptide ‘lifts’ its amino-terminus partly away from the HLA peptide binding groove, forming a higher affinity interface with the TCR than is formed with the anchor residue ‘optimised’ heteroclitic peptide, which cannot be ‘pulled’ from the HLA groove.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recognition of pathogen-derived nucleic acids by immune cells is critical for the activation of protective innate immune responses. Bacterial cyclic dinucleotides (CDNs) are small nucleic acids that are directly recognized by the cytosolic DNA sensor STING, initiating a response characterized by pro-inflammatory cytokine and type I interferon production. Strategies to improve the immune stimulatory activities of CDNs can further their potential for clinical development. Here, we demonstrate that a simple complex of cylic-di-GMP with a cell-penetrating peptide enhances both cellular delivery and biological activity of the cyclic-di-GMP in murine splenocytes. Furthermore, our findings establish that activation of the TLR-dependent and independent DNA recognition pathways through combined use of CpG oligonucleotide (ODN) and CDN results in synergistic activity, augmenting cytokine production (IFNα/β, IL-6, TNF-α, IP-10), co-stimulatory molecule upregulation (MHC class II, CD86) and antigen-specific humoral and cellular immunity. Results presented herein indicate that 3’3’-cGAMP, a recently identified bacterial CDN, is a superior STING ligand than c-di-GMP in human PBMCs. Collectively, these findings suggest that the immune-stimulatory properties of CDNs can be augmented through peptide complexation or synergistic use with CpG ODN and may be of interest for the development of cyclic dinucleotide-based immunotherapeutic agents.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms by which squalene, which in oil-and-water emulsions has been shown to be an excellent formulation for TLR agonists, enhances the magnitude and quality of adaptive immune responses are not thoroughly defined. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2015. 45: XXXX-XXXX], Desbien et al. show that a squalene/TLR4-based adjuvant augments antigen-specific Th1 responses in vaccinated mice through a caspase/IL-18-dependent mechanism. This commentary will discuss the authors’ findings in the context of elucidating the mechanism of action of squalene as an adjuvant, and the new questions that the work generates.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: T cells chronically stimulated by a persistent antigen often become dysfunctional and lose effector functions and proliferative capacity. To identify the importance of microRNA-155 (miR-155) in this phenomenon, we analyzed mouse miR-155-deficient CD4+ T cells in a model where the chronic exposure to a systemic antigen led to T-cell functional unresponsiveness. We found that miR-155 was required for restoring function of T cells after programmed death receptor 1 (PD-1) blockade. Heme oxygenase 1 (HO-1) was identified as a specific target of miR-155 and inhibition of HO-1 activity restored the expansion and tissue migration capacity of miR-155−/− CD4+ T cells.. Moreover, miR-155-mediated control of HO-1 expression in CD4+ T cells was shown to sustain in vivo antigen-specific expansion and IL-2 production. Thus, our data identify HO-1 regulation as a mechanism by which miR-155 promotes T cell-driven inflammation.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although the strategic production of prolactin-inducible protein (PIP) at several ports of pathogen entry into the body suggests it might play a role in host defense, no study has directly implicated it in immunity against any infectious agent. Here, we show for the first time that PIP deficiency is associated with reduced numbers of CD4+ T cells in peripheral lymphoid tissues and impaired CD4+ Th1-cell differentiation in vitro. In vivo, CD4+ T cells from OVA-immunized, PIP-deficient mice showed significantly impaired proliferation and IFN-γ production following in vitro restimulation. Furthermore, PIP-deficient mice were highly susceptible to L. major infection and failed to control lesion progression and parasite proliferation. This susceptibility was associated with impaired nitric oxide production and leishmaniacidal activity of PIP KO macrophages following IFN-γ and LPS stimulation. Collectively, our findings implicate PIP as an important regulator of CD4+ Th1 cell-mediated immunity.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • European Journal of Immunology 01/2015; 45(1).
  • Susan A. Olalekan, Yanxia Cao, Keith M. Hamel, Alison Finnegan
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical efficacy in the treatment of rheumatoid arthritis with anti-CD20 (Rituximab)-mediated B-cell depletion has garnered interest in the mechanisms by which B cells contribute to autoimmunity. We have reported that B-cell depletion in a murine model of proteoglycan-induced arthritis (PGIA) leads to an increase in regulatory T (Treg) cells that correlates with decreased autoreactivity. Here, we demonstrate that the increase in Treg cells after B-cell depletion is due to an increase in the differentiation of naïve CD4+ T cells into Treg cells. Since the development of PGIA is dependent on IFN-γ and B cells are reported to produce IFN-γ, we hypothesized that B-cell-specific IFN-γ plays a role in the development of PGIA. Accordingly, mice with B-cell-specific IFN-γ-deficiency were as resistant to the induction of PGIA as mice that were completely IFN-γ-deficient. Importantly, despite a normal frequency of IFN-γ-producing CD4+ T cells, B-cell-specific IFN-γ-deficient mice exhibited a higher percentage of Treg cells compared with that in wild type (WT) mice. These data indicate that B-cell IFN-γ production inhibits Treg-cell differentiation and exacerbates arthritis. Thus, we have established that IFN-γ, specifically derived from B cells, uniquely contributes to the pathogenesis of autoimmunity through prevention of immunoregulatory mechanisms.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • Ilaria Tassi, Nimisha Rikhi, Estefania Claudio, Hongshan Wang, Wanhu Tang, Hye‐lin Ha, Sun Saret, Daniel H. Kaplan, Ulrich Siebenlist
    [Show abstract] [Hide abstract]
    ABSTRACT: Bcl-3 is an atypical member of the IκB family. Bcl-3 functions as a cofactor of p50/NF-κB1 or p52/NF-κB2 homodimers in nuclei, where it modulates NF-κB-regulated transcription in a context-dependent way. Bcl-3 has tumorigenic potential, is critical in host defense of pathogens, and has been reported to ameliorate or exacerbate inflammation, depending on disease model. However, cell-specific functions of Bcl-3 remain largely unknown. Here, we explored the role of Bcl-3 in a contact hypersensitivity (CHS) mouse model, which depends on the interplay between keratinocytes and immune cells. Bcl-3-deficient mice exhibited an exacerbated and prolonged CHS response to oxazolone. Increased inflammation correlated with higher production of chemokines CXCL2, CXCL9 and CXCL10, and consequently increased recruitment of neutrophils and CD8+ T cells. Bone marrow chimera experiments indicated that the ability of Bcl-3 to reduce the CHS response depended on Bcl-3 activity in radioresistant cells. Specific ablation of Bcl-3 in keratinocytes resulted in increased production of CXCL9 and CXCL10 and sustained recruitment of specifically CD8+ T cells. These findings identify Bcl-3 as a critical player during the later stage of the CHS reaction to limit inflammation via actions in radioresistant cells, including keratinocytes.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: 5´-nucleotidase/CD73 is a key enzyme in the regulation of purinergic signaling, hydrolyzing extracellular AMP to produce adenosine, which is critical in the blood vascular system and in immunosuppression. CD73 is expressed by both blood endothelial cells and lymphatic endothelial cells. Although the role of CD73 on blood endothelial cells in controlling vascular permeability and leukocyte trafficking has been studied, the role of lymphatic CD73 has thus far remained unknown. In this issue of European Journal of Immunology, Yegutkin et al. [Eur. J. Immunol. 2015. 45: XXXX-XXXX] compare CD73 activity in the endothelia of lymphatics and blood vessels and investigate the CD73+ lymphocyte subpopulations possibly involved in immunoregulation. This Commentary will discuss how the authors’ work sheds light on the differential use of CD73 by these two cell populations to control endothelial permeability and sprouting.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thymus colonisation and thymocyte positioning are regulated by interactions between CCR7 and CCR9, and their respective ligands, CCL19/CCL21 and CCL25. The ligands of CCR7 and CCR9 also interact with the atypical receptor CCRL1 (also known as ACKR4), which is expressed in the thymus and has recently been reported to play an important role in normal αβT-cell development. Here, we show that CCRL1 is expressed within the thymic cortex, predominantly by MHC-II(low) CD40(-) cortical thymic epithelial cells (TECs) and at the subcapsular zone by a population of podoplanin(+) TECs in mice. Interestingly, CCRL1 is also expressed by stromal cells which surround the pericytes of vessels at the corticomedullary junction, the site for progenitor cell entry and mature thymocyte egress from the thymus. We show that CCRL1 suppresses thymocyte progenitor entry into the thymus, however, the thymus size and cellularity are the same in adult wild-type and CCRL1(-/-) mice. Moreover, CCRL1(-/-) mice have no major perturbations in T-cell populations at different stages of thymic differentiation and development, and have a similar rate of thymocyte migration into the blood. Collectively, our findings argue against a major role for CCRL1 in normal thymus development and function. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Targeting antigens to dendritic cell (DC) surface receptors using antibodies has been successfully used to generate strong immune responses and is currently in clinical trials for cancer immunotherapy. Whilst cancer immunotherapy focuses on the induction of CD8(+) T-cell responses, many successful vaccines to pathogens or their toxins utilize humoral immunity as the primary effector mechanism. Universally, these approaches have used adjuvants or pathogen material that augment humoral responses. However, adjuvants are associated with safety issues. One approach, successfully used in the mouse, to generate strong humoral responses in the absence of adjuvant is to target antigen to Clec9A, also known as DNGR-1, a receptor on CD8α(+) DCs. Here, we address two issues relating to clinical application. First, we address the issue of variable adjuvant-dependence for different antibodies targeting mouse Clec9A. We show that multiple sites on Clec9A can be successfully targeted, but that strong in vivo binding and provision of suitable helper T cell determinants was essential for efficacy. Second, we show that induction of humoral immunity to CLEC9A-targeted antigens is extremely effective in non-human primates, in an adjuvant-free setting. Our findings support extending this vaccination approach to humans and offer important insights into targeting design. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin (IL)-17 and IL-22 have been reported to play critical roles in autoimmunity and inflammation but information about their role in cancer is limited. In this study, we investigated the role of IL-17 and IL-22 in the progression of human skin basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). We found that both tumor types are infiltrated with an high number of IL-17(+) and IL-22(+) T lymphocytes, as demonstrated by immunohistochemistry and by FACS analysis performed on peritumoral T-cell lines isolated from skin biopsies. In vitro studies demonstrated that proliferation and migration of the BCC and SCC cell lines M77015 and CAL27 were increased by IL-17 and IL-22. Moreover, IL-17, alone or in combination with TNF-α, was able to induce the production of two cytokines important for tumor progression, IL-6 and IL-8, in CAL27. We also showed that IL-17 upregulated NF-κB signaling, while IL-22 activated the STAT3 pathway and the anti-apoptotic AKT protein in M77015 and CAL27. Finally, in vivo experiments demonstrated that IL-17 and IL-22 enhanced tumor growth in nude mice injected with CAL27. Altogether, our findings indicate that high levels of IL-22 and IL-17 in the BCC and SCC microenvironment promote tumor progression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antigen (Ag) delivery to specific antigen-presenting cells (APCs) is an attractive approach in developing strategies for vaccination. CD169(+) macrophages in the marginal zone of the spleen represent a suitable target for delivery of Ag because of their strategic location, which is optimal for the capture of blood-borne Ag and their close proximity to B cells and T cells in the white pulp. Here we show that Ag targeting to CD169(+) macrophages in mice resulted in strong, isotype switched, high affinity antibody (Ab) production and the preferential induction and long term persistence of Ag-specific germinal center (GC) B cells and follicular T helper (Tfh) cells. In agreement with these observations, CD169(+) macrophages retained intact Ag, induced cognate activation of B cells and increased expression of co-stimulatory molecules upon activation. In addition, macrophages were required for the production of cytokines that promote B-cell responses. Our results identify CD169(+) macrophages as promoters of high affinity humoral immune responses and emphasize the value of CD169 as target for Ag delivery to improve vaccine responses. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human CD8(+) T cells are functionally heterogeneous and can be divided into phenotypically and functionally distinct subsets according to CCR7 and CD45RA expression levels. Among these, CCR7(low) CD45RA(low) effector memory CD8(+) T cells (Tem) and CCR7(low) CD45RA(high) CD8(+) T cells, which are designated as Temra and considered to be terminally differentiated cells, are antigen-experienced T cells but show different functionalities. Here, we show that, while Tem proliferate vigorously and produce IFN-γ persistently and robustly, Temra proliferate poorly and lose the ability to produce IFN-γ over time after TCR stimulation. Temra showed impaired cell growth upon TCR stimulation, which was associated with defective activation of the mammalian target of rapamycin (mTOR) signaling. Furthermore, rapamycin, an inhibitor of mTOR signaling, interfered with the robust and continuous proliferation of and IFN-γ production by Tem at later time points after TCR stimulation. Thus, these data collectively indicate that activation of mTOR signaling is required for the robust functions of Tem cells in humans and suggest that defective mTOR signaling in Temra contributes to their functional impairment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 12/2014;