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  • 1.
    Belz, Gabrielle T
    et al.
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Behrens, Georg M N
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Smith, Chris M
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Miller, Jacques F A P
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Jones, Claerwen
    Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
    Lejon, Kristina
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Fathman, C. Garrison
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Mueller, Scott N
    Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
    Shortman, Ken
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Carbone, Francis R
    Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
    Heath, William R
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    The CD8alpha+ dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens.2002In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 196, no 8, p. 1099-1104Article in journal (Refereed)
    Abstract [en]

    We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow-derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8alpha(+) dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced beta-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c(+)CD8alpha(+) cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8alpha(+) DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self.

  • 2. Björkström, Niklas K
    et al.
    Lindgren, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Stoltz, Malin
    Fauriat, Cyril
    Braun, Monika
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Michaëlsson, Jakob
    Malmberg, Karl-Johan
    Klingström, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ljunggren, Hans-Gustaf
    Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus2011In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 208, no 1, p. 13-21Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.

  • 3. Coppi, Alida
    et al.
    Natarajan, Ramya
    Pradel, Gabriele
    Bennett, Brandy L.
    James, Eric R.
    Roggero, Mario A.
    Corradin, Giampietro
    Persson, Cathrine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Tewari, Rita
    Sinnis, Photini
    The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host2011In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 208, no 2, p. 341-356Article in journal (Refereed)
    Abstract [en]

    Plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. The sporozoite's major surface protein, circumsporozoite protein (CSP), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. In this study, we show that CSP has two conformational states, an adhesive conformation in which the C-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the N terminus masks this domain. We demonstrate that the cell-adhesive domain functions in sporozoite development and hepatocyte invasion. Between these two events, the sporozoite must travel from the mosquito midgut to the mammalian liver, and N-terminal masking of the cell-adhesive domain maintains the sporozoite in a migratory state. In the mammalian host, proteolytic cleavage of CSP regulates the switch to an adhesive conformation, and the highly conserved region I plays a critical role in this process. If the CSP domain architecture is altered such that the cell-adhesive domain is constitutively exposed, the majority of sporozoites do not reach their target organs, and in the mammalian host, they initiate a blood stage infection directly from the inoculation site. These data provide structure-function information relevant to malaria vaccine development.

  • 4. Feldhahn, Niklas
    et al.
    Henke, Nadine
    Melchior, Kai
    Duy, Cihangir
    Soh, Bonaventure Ndikung
    Klein, Florian
    von Levetzow, Gregor
    Giebel, Bernd
    Li, Ai-Hong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hofmann, Wolf-Karsten
    Jumaa, Hassan
    Müschen, Markus
    Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells2007In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 204, no 5, p. 1157-1166Article in journal (Refereed)
    Abstract [en]

    The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. ALL cells are derived from B cell precursors in most cases and typically carry rearranged immunoglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph(+) ALLs as compared with 6 of 80 Ph(-) ALLs. Forced expression of BCR-ABL1 in Ph(-) ALL cells and inhibition of the BCR-ABL1 kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph(+) ALL, IGH V region genes and BCL6 were mutated in many Ph(+) but unmutated in most Ph(-) cases. In addition, AID introduced DNA single-strand breaks within the tumor suppressor gene CDKN2B in Ph(+) ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph(+) ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset.

  • 5.
    Trageser, Daniel
    et al.
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Iacobucci, Ilaria
    Department of Hematology/Oncology “L. and A. Seràgnoli,” University of Bologna, Italia.
    Nahar, Rahul
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Duy, Cihangir
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    von Levetzow, Gregor
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Klemm, Lars
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Park, Eugene
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Schuh, Wolfgang
    Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, Germany.
    Gruber, Tanja
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Herzog, Sebastian
    Max-Planck Institute for Immunobiology, D-79108 Freiburg, Germany .
    Kim, Yong-mi
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Hofmann, Wolf-Karsten
    Department of Hematology and Oncology, University Hospital Mannheim, Germany.
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Storlazzi, Clelia Tiziana
    Department of Genetics and Microbiology, University of Bari, Italy.
    Jäck, Hans-Martin
    Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, Germany.
    Groffen, John
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Martinelli, Giovanni
    Department of Hematology/Oncology “L. and A. Seràgnoli,” University of Bologna, Italy.
    Heisterkamp, Nora
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Jumaa, Hassan
    Max-Planck Institute for Immunobiology, D-79108 Freiburg, Germany .
    Müschen, Markus
    Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.
    Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function2009In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 206, no 8, p. 1739-1753Article in journal (Refereed)
    Abstract [en]

    B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre-B cell receptor-dependent stages. The Philadelphia chromosome-positive (Ph(+)) subtype of ALL accounts for 25-30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre-B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph(+) ALL cells. Pre-B cell receptor-mediated cell cycle arrest in Ph(+) ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, even if expression of the pre-B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre-B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph(+) ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre-B cell receptor-mediated tumor suppression.

  • 6. Zhang, Ming
    et al.
    Alicot, Elisabeth M
    Chiu, Isaac
    Li, Jinan
    Verna, Nicola
    Vorup-Jensen, Thomas
    Kessler, Benedikt
    Shimaoka, Motomu
    Chan, Rodney
    Friend, Daniel
    Mahmood, Umar
    Weissleder, Ralph
    Moore, Francis D
    Carroll, Michael C
    Identification of the target self-antigens in reperfusion injury.2006In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 203, no 1, p. 141-52Article in journal (Refereed)
    Abstract [en]

    Reperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heavy chain type II A and C as the self-targets in two different tissues. These results identify a novel pathway in which the innate response to a highly conserved self-antigen expressed as a result of hypoxic stress results in tissue destruction.

  • 7.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Cold Spring Harbor Laboratory and Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
    Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer2017In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 214, no 3, p. 579-596Article in journal (Refereed)
    Abstract [en]

    Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of a-smooth muscle actin (alpha SMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated aSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

  • 8. Öhlund, Daniel
    et al.
    Elyada, Ela
    Tuveson, David
    Fibroblast heterogeneity in the cancer wound2014In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 211, no 8, p. 1503-1523Article, review/survey (Refereed)
    Abstract [en]

    Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.

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