Klas Kärre Group
Our group has formulated the missing self hypothesis for NK cell recognition, and established a number of experimental models to test and further develop this concept. This original hypothesis states that NK cells can identify abnormal cells by sensing absence or inadequate expression of self MHC class I molecules.
Human Cytomegalovirus (HCMV) is a double-stranded DNA-virus, belonging to the herpes viruses. In western countries it infects between 70-80% of the population, usually early in life. Infection under normal circumstances is asymptomatic but the virus establishes life-long latency in the host. Under certain conditions, such as immunosuppression (during cytostatic therapy, transplantation protocols or in AIDS patients), reactivation can occur and give rise to serious or even life-threatening consequences.
However the most fascinating question is how CMV escapes the host immune response for decades and how this fine-tuned equilibrium with the immune system is established. In a permanent co-evolution with the host, CMV evolved a wide array of immunoevasive strategies targeting the immune response on multiple stages. It is estimated that more than 30 viral genes serve the purpose of facilitating immune escape.
CD8+ T cells are known to be crucial for control of the virus, both during primary infection as well as during episodes of reactivation. HCMV has devoted a considerable number of genes ( e.g. US2, US3, US6 and US11, all of which have a different mode of action) to downmodulate MHC class I molecules which, in complex with CMV-derived peptides serve as recognition structures for CD8+ T cells. But the event of MHC class I downmodulation should theoretically render infected cells highly susceptible to NK-cell mediated responses (missing-self recognition, see main page). Yet several groups including our own have reported an even decreased sensitivity to NK cell cytotoxicity after infection of cells with CMV (!) This intriguing finding constitutes the fascinating core question of NK cell - CMV biology (see also cartoon).
To escape NK cells, even in face of markedly reduced MHC class I expression, the virus conceptually has two options:
- The delivery of an alternative inhibitory signal to the NK cell (e.g. by virtue of viral class I homologues)
- The interference with NK cell activating pathways.
Both alternatives are under investigation in our laboratory.
Former Group Members
NK, T and Dendritic Cells
Hans-Gustav Ljunggren, Center for Infectious Medicine, CIM Karolinska Institutet, Department of Medicine, Huddinge University Hospital, Stockholm, Sweden.
Tumor Immunology, T-cells and Epitopes
Rolf Kiessling, CCK, Karolinska Unviersity Hospital, Solna, Sweden.
Charles Sentman, Immunology, Dartmouth Medical School, Dartmouth College, Hanover, NH, USA.
Protein Expression, Purification and Crystallography
Bob Harris, Neuroimmunology, Center for Molecular Medicine CMM, Karolinska Institutet, Sweden.
NK Cells and Cytomegalovirus
Wayne Yokoyama, Howard Hughes Medical Institute, Rheumatology Division, Department of Medicine, Washington University School of Medicine and Barnes Jewish Hospital, St. Louis, Missouri, USA.
Gerdt Riise, Department of Clinical Virology, Göteborg University, Sahlgrenska Hospital, Göteborg, Sweden.
Annika Linde, SMI/Karolinska Institutet, Stockholm, Sweden.
Cecilia Söderberg-Naucler, Cell and Molecular Immunology, Center for Molecular Medicine CMM, Karolinska Institutet, Sweden.
Eric Vivier, Centre d'Immunologie, INSERM-CNRS de Marseille Luminy, Parc Scientifique de Luminy - Case 906, 13288 Marseille Cedex 9, France.
David Cosman, Molecular Biology, AMGEN Corporation, Seattle, Washington, USA.
Associates and Funding
- Viktor Levitsky; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet (Pdf file, 199 Kb)
- Ramit Mehr; Faculty of Life Sciences, Bar-Ilan University, Israel
- Sven Pettersson, MTC, Karolinska Institutet
- Gunter Schneider; Medical Biochemistry and Biophysics (MBB), Karolinska Institutet
- Laszlo Szekely Group, MTC, Karolinska Institutet
- Ennio Carbone, Department of Experimental and Clinical Medicine "G. Salvatore", University of Catanzaro Magna Graecia, Italy
- Cristina Cerboni, Department of Experimental Medicine and Pathology, Policlinico "Umberto I",University "La Sapienza",Rome,Italy
- Stiftelsen för stategisk forskning
- Novo nordisk
- Göran Gustafsson stiftelse
- Svenska sällskapet för medicinsk forskning
- Karolinska Institutet
- Svenska Läkaresällskapet
- Tobias stiftlesen
- Stiftelsen Lars Hiertas Minne (Foundation of Lars Hierta's Memory)
- Alex och Ewa Wallströms Stiftelse (Alex and Ewa Wallströms Foundation)
- Robert Lundbergs Minnesstiftelse (Robert Lundberg Memorial Fund)
- Åke Wibergs Stiftelse (Åke Wiberg's Foundation)
- Arbetsmarknadens Försäkringsaktiebolag
Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition.
Sottile R, Federico G, Garofalo C, Tallerico R, Faniello MC, Quaresima B, et al
Front Immunol 2019 ;10():224
Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway.
Cristiani CM, Turdo A, Ventura V, Apuzzo T, Capone M, Madonna G, et al
Cancer Immunol Res 2019 05;7(5):841-852
2017 & 2018
Expression of CD226 is associated to but not required for NK cell education
Arnika K. Wagner, Nadir Kadri, Johanna Snäll, Petter Brodin, Susan Gilfillan, Marco Colonna, Günter Bernhardt, Petter Höglund, Klas Kärre & Benedict J. Chambers
Nature Communications 8, Article number: 15627 (2017) doi:10.1038/ncomms15627
IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients.
Tallerico R, Cristiani CM, Staaf E, Garofalo C, Sottile R, Capone M, et al
Oncoimmunology 2017 ;6(2):e1261242
George Klein (1925-2016).
Ernberg I, Kärre K, Wigzell H
Nature 2017 02;542(7641):296
Independent control of natural killer cell responsiveness and homeostasis at steady-state by CD11c+ dendritic cells.
Luu TT, Ganesan S, Wagner AK, Sarhan D, Meinke S, Garbi N, et al
Sci Rep 2016 12;6():37996
Herpes simplex virus specific T cell response in a cohort with primary genital infection correlates inversely with frequency of subsequent recurrences.
Franzen-Röhl E, Schepis D, Atterfelt F, Franck K, Wikström A, Liljeqvist JÅ, et al
Sex Transm Infect 2017 05;93(3):169-174
IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo.
Kritikou JS, Dahlberg CI, Baptista MA, Wagner AK, Banerjee PP, Gwalani LA, et al
Sci Rep 2016 08;6():30636
In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation.
Lakshmikanth T, Heuts F, Muvva SS, Wallin RP, Persson AK, Fauriat C, et al
Eur J Immunol 2016 07;46(7):1758-69
Microchip Screening Platform for Single Cell Assessment of NK Cell Cytotoxicity.
Guldevall K, Brandt L, Forslund E, Olofsson K, Frisk TW, Olofsson PE, et al
Front Immunol 2016 ;7():119
Dynamic Regulation of NK Cell Responsiveness.
Kadri N, Wagner AK, Ganesan S, Kärre K, Wickström S, Johansson MH, et al
Curr Top Microbiol Immunol 2016 ;395():95-114
Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response.
Wagner AK, Wickström SL, Tallerico R, Salam S, Lakshmikanth T, Brauner H, et al
Cancer Immunol Res 2016 Feb;4(2):113-23
HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors.
Sottile R, Pangigadde PN, Tan T, Anichini A, Sabbatino F, Trecroci F, et al
Eur J Immunol 2016 Feb;46(2):409-19
Depletion of IL-2 receptor β-positive cells protects from diabetes in non-obese diabetic mice.
Brauner H, Hall HT, Flodström-Tullberg M, Kärre K, Höglund P, Johansson S
Immunol Cell Biol 2016 Feb;94(2):177-84
Enrichment of CD56(dim)KIR + CD57 + highly cytotoxic NK cells in tumour-infiltrated lymph nodes of melanoma patients.
Ali TH, Pisanti S, Ciaglia E, Mortarini R, Anichini A, Garofalo C, et al
Nat Commun 2014 Dec;5():5639
A genetic defect in mice that impairs missing self recognition despite evidence for normal maturation and MHC class I-dependent education of NK cells.
Wickström SL, Öberg L, Kärre K, Johansson MH
J Immunol 2014 Feb;192(4):1577-86
Natural killer cell inhibitory receptor expression in humans and mice: a closer look.
Sternberg-Simon M, Brodin P, Pickman Y, Onfelt B, Kärre K, Malmberg KJ, et al
Front Immunol 2013 ;4():65
Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules.
Tallerico R, Todaro M, Di Franco S, Maccalli C, Garofalo C, Sottile R, et al
J Immunol 2013 Mar;190(5):2381-90
Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice.
Li Y, Kundu P, Seow SW, de Matos CT, Aronsson L, Chin KC, et al
Carcinogenesis 2012 Jun;33(6):1231-8
Expansion of T-cells from the cord blood graft as a predictive tool for complications and outcome of cord blood transplantation.
Gertow J, Berglund S, Okas M, Kärre K, Remberger M, Mattsson J, et al
Clin Immunol 2012 May;143(2):134-44
Skewing of the NK cell repertoire by MHC class I via quantitatively controlled enrichment and contraction of specific Ly49 subsets.
Brodin P, Lakshmikanth T, Kärre K, Höglund P
J Immunol 2012 Mar;188(5):2218-26
First International Meeting of the Thematic Centre for Immune Modulatory Therapies for Autoimmunity and Cancer (IMTAC) 13-14 June 2011, Ljusterö, Sweden.
Choudhury A, Höglund P, Kiessling R, Kärre K, Lundqvist A, Malmberg K, et al
Cancer Immunol Immunother 2012 Apr;61(4):587-91
Syntaxin 11 marks a distinct intracellular compartment recruited to the immunological synapse of NK cells to colocalize with cytotoxic granules.
Dabrazhynetskaya A, Ma J, Guerreiro-Cacais AO, Arany Z, Rudd E, Henter JI, et al
J Cell Mol Med 2012 Jan;16(1):129-41
Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2.
Li H, Lakshmikanth T, Garofalo C, Enge M, Spinnler C, Anichini A, et al
Cell Cycle 2011 Oct;10(19):3346-58
NK cell function and antibodies mediating ADCC in HIV-1-infected viremic and controller patients.
Johansson SE, Rollman E, Chung AW, Center RJ, Hejdeman B, Stratov I, et al
Viral Immunol 2011 Oct;24(5):359-68
Increased cell-mediated immune responses in patients with recurrent herpes simplex virus type 2 meningitis.
Franzen-Röhl E, Schepis D, Lagrelius M, Franck K, Jones P, Liljeqvist JÅ, et al
Clin Vaccine Immunol 2011 Apr;18(4):655-60
Immunology Journals (Impact factors according to ISI citation report)
Nature Immunology (28.2)
Journal of Experimental Medicine (15.3)
Journal of Clinical Investigation (14.3)
Journal of Immunology (6.7)
European Journal of Immunology (4.5)
International Immunology (3.7)
Genes and Immunity (3.6)
Molecular Immunology (2.8)
Human Immunology (2.6)
Scandinavian Journal of Immunology (1.9)