Gunilla Karlsson Hedestam Group

_{From left to right: Mateusz Kaduk, Afrin Chowdhury, Ganesh Phad, Monika Àdori, Juliette Soulier, Marco Mandolesi, Gunilla Karlsson Hedestam, Nèstor Vázquez-Bernat, Pradeepa Pushparaj, Uta Hardt, Sharesta Khoenkhoen, Martin Corcoran and Sanjana Narang. Missing from picture: Elina Erikson}

Research Description

Genetic basis for B cell recognition and function
Our research focuses on the function of B lymphocytes and qualitative aspects of immunological memory. We study the role of specific pathways affecting B cell development or function to understand processes that regulate B cell selection and differentiation. In several projects, we define antibody responses at the clonal level by single-cell sorting memory B cells for sequence analysis of antibody V(D)J transcripts and for isolation of antigen-specific monoclonal antibodies. We also apply next generation sequencing to analyze expressed immune repertoires and to trace specific antibody lineages to understand their fate and levels of affinity maturation. Because V(D)J gene assignment is a critical first step of lineage tracing, and there is considerable genetic variation in germline V genes/alleles between subjects, we developed a computational tool that allows the generation of individualized germline V gene databases, IgDiscover. This is a major technical advance that will enable the use of individualized germline databases to become a standard element of high quality immunological studies in both humans and experimental animals. By applying these methods we obtain new and highly detailed information about the establishment of long-lived immunity.

IgDiscover

Access a computational tool that allows i) the generation of individualized germline immunoglobulin gene databases and ii) analysis of expressed antibody repertoires.

IgDiscover website

Projects

B cell repertoire analysis following immunization

Isolation and analysis of vaccine-elicited monoclonal antibodies

Mechanistic studies of mice with defects in humoral immune responses

Selected Publications

TACI expression and plasma cell differentiation are impaired in the absence of functional IκBNS.
Khoenkhoen S, Erikson E, Ádori M, Stark J, Scholz J, Cancro M, et al
Immunol. Cell Biol. 2018 Dec;():

Targeted N-glycan deletion at the receptor-binding site retains HIV Env NFL trimer integrity and accelerates the elicited antibody response.
Dubrovskaya V, Guenaga J, de Val N, Wilson R, Feng Y, Movsesyan A, et al
PLoS Pathog. 2017 Sep;13(9):e1006614

Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach.
Martinez-Murillo P, Tran K, Guenaga J, Lindgren G, Àdori M, Feng Y, et al
Immunity 2017 05;46(5):804-817.e7

Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity.
Corcoran M, Phad G, Vázquez Bernat N, Stahl-Hennig C, Sumida N, Persson M, et al
Nat Commun 2016 12;7():13642

Heterozygous Mutation in IκBNS Leads to Reduced Levels of Natural IgM Antibodies and Impaired Responses to T-Independent Type 2 Antigens.
Pedersen G, Ádori M, Stark J, Khoenkhoen S, Arnold C, Beutler B, et al
Front Immunol 2016 ;7():65

Diverse antibody genetic and recognition properties revealed following HIV-1 envelope glycoprotein immunization.
Phad G, Vázquez Bernat N, Feng Y, Ingale J, Martinez Murillo P, O'Dell S, et al
J. Immunol. 2015 Jun;194(12):5903-14

B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS.
Pedersen G, Àdori M, Khoenkhoen S, Dosenovic P, Beutler B, Karlsson Hedestam G
Proc. Natl. Acad. Sci. U.S.A. 2014 Sep;111(39):E4119-26

Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants.
Klein F, Nogueira L, Nishimura Y, Phad G, West A, Halper-Stromberg A, et al
J. Exp. Med. 2014 Nov;211(12):2361-72

HIV-1 receptor binding site-directed antibodies using a VH1-2 gene segment orthologue are activated by Env trimer immunization.
Navis M, Tran K, Bale S, Phad G, Guenaga J, Wilson R, et al
PLoS Pathog. 2014 Aug;10(8):e1004337

Single-cell and deep sequencing of IgG-switched macaque B cells reveal a diverse Ig repertoire following immunization.
Sundling C, Zhang Z, Phad G, Sheng Z, Wang Y, Mascola J, et al
J. Immunol. 2014 Apr;192(8):3637-44

Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign.
Tran K, Poulsen C, Guenaga J, de Val N, de Val Alda N, Wilson R, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Feb;111(7):E738-47

A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity.
Arnold C, Pirie E, Dosenovic P, McInerney G, Xia Y, Wang N, et al
Proc. Natl. Acad. Sci. U.S.A. 2012 Jul;109(31):12286-93

High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site.
Sundling C, Li Y, Huynh N, Poulsen C, Wilson R, O'Dell S, et al
Sci Transl Med 2012 Jul;4(142):142ra96

Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates.
Sundling C, Forsell M, O'Dell S, Feng Y, Chakrabarti B, Rao S, et al
J. Exp. Med. 2010 Aug;207(9):2003-17

The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus.
Karlsson Hedestam G, Fouchier R, Phogat S, Burton D, Sodroski J, Wyatt R
Nat. Rev. Microbiol. 2008 Feb;6(2):143-55

Further publications

Further Publications 2005-2015 on PubMed

Further Publications before 2005 on PubMed

Group Members

	Martin Corcoran	Senior research specialist	Martin.Corcoran@ki.se 08-524 869 43
	Elina Erikson	Postdoc	elina.erikson@ki.se 08-524 869 52
	Mateusz Kaduk	Postdoc	mateusz.kaduk@ki.se
	Gunilla Karlsson Hedestam	Professor	Gunilla.Karlsson.Hedestam@ki.se 08-524 869 55
	Sharesta Khoenkhoen	PhD student, Graduate Student	sharesta.khoenkhoen@ki.se
	Martina Löfstedt Jalava	Coordinator	Martina.Jalava.Lofstedt@ki.se 08-524 845 13
	Marco Mandolesi	PhD student, Graduate Student	marco.mandolesi@ki.se
	Benjamin Murrell	Assistant professor	benjamin.murrell@ki.se
	Sanjana Narang	PhD student, Graduate Student	sanjana.narang@ki.se
	Izabela Nowak	Associated	izabela.nowak@ki.se
	Ganesh Phad	PhD student	ganesh.phad@ki.se 08-524 869 43
	Pradeepa Pushparaj	PhD student, Graduate Student	pradeepa.pushparaj@ki.se
	Néstor Vázquez Bernat	PhD student, Graduate Student	nestor.vazquez.bernat@ki.se
	Monika Àdori	Senior research specialist	monika.adori@ki.se 08-524 869 46

Associated Researchers

Uta Hardt

Alumni

PhD students (name and year of graduation)

Main supervisor:

Åsa Hidmark, 2007
Opponent: Bruce Beutler
Åsa defended her PhD in 2007 after which she received the Jonas Söderqvist’s Prize for basic research in virology and immunology. Åsa moved on to a post-doctoral position at the University of Heidelberg in Germany, where she is now active as a senior research scientist in the field of immunology and diabetes.

Mattias Forsell, 2008
Opponent: Quentin Sattentau
Mattias defended his PhD in 2008. Part of his doctoral research was carried out at the National Institutes of Health in Washington. After this, he received an Early career investigator AMFAR award for post-doctoral work, which was carried out at Karolinska Institutet. He recently obtained a position as Assistant Professor at Umeå University where he now leads his own research group.

Pia Dosenovic, 2012
Opponent: Michael McHeyzer-Williams
Pia defended her PhD in 2012 after which she obtained 3 years of funding from the Swedish Research Council to pursue a post-doc at the Rockefeller University in New York. Pia is currently active in several research consortia including CHAVI-ID, as a member of the Nussenzweig laboratory.

Christopher Sundling, 2012
Opponent: Robin Weiss
Christopher defended his PhD in 2012 and in the last year of his studies he was awarded the Dimitris N. Chorafas Foundation Prize. He subsequently also received the Jonas Söderqvist’s Prize for basic research in virology and immunology and Sven Gard’s prize for best thesis in virology. He then moved on to a post-doc position in the Brink laboratory at the Garvan Institute in Sydney and returned in 2017 to establish his own group at the Department of Medicine, Solna as an Assistant Professor.

Paola Martinez Murillo, 2017
Opponent: Leo Stamatatos
Paola defended her PhD in May of 2017. During her doctoral education she collaborated closely with scientists at the Scripps Research Institute in La Jolla and she spent a month as a visiting student at the Rockefeller University. An additional initiative she took was to teach Immunology to young students in Colombia, two summers in a row. Her Immunity paper published just before her PhD defense received “Best paper of the year” at MTC 2017.

Martina Soldemo, 2017
Opponent: Klaus Überla
Martina defended her PhD in October of 2017 after a productive time as a doctoral student. In addition to her own projects, she was instrumental to many collaborations both within and outside the lab and she contributed enthusiastically to teaching at both the undergraduate and post-graduate level at KI.

Ganesh Phad, 2018
Opponent: Stephen Quake
Ganesh defended his PhD in June 2018. During his doctoral studies, he applied a broad set of techniques to study B cell responses and immunization-induced monoclonal antibodies. He was instrumental in setting up Next Generation Sequencing methodology for analyses of antibody repertoires and, together with Martin Corcoran in the group and computational scientist Marcel Martin, developed the broadly applicable IgDiscover tool. Ganesh gave talks at several international meetings during his PhD training and he currently stays on in the group as a post-doctoral fellow.

Co-supervisor:
Cornelia Gujer, 2011
Kai Eng, 2012
Lina Josefsson, 2013
Lotta Pramanik Sollerkvist, 2014
Faezzah Baharom 2016
Katrin Habir 2018

MSc students (name and year of graduation)

Christopher Sundling, 2007
Martina Soldemo, 2009
Nick Huynh, 2011
Max Reiss, 2011
Flavio Lombardo, 2013
Néstor Vázquez Bernat, 2014
Sharesta Khoenkhoen, 2014

Previous post-docs

Lotta Pramanik
Iyadh Douagi
Marjon Navis
Gabriel Pedersen

Collaborations

International collaborators
John Mascola, Vaccine Research Center, NIH
Richard Wyatt, The Scripps Research Center
Michael Cancro, University of Pennsylvania
Lynn Morris, Johannesburg
Bruce Beutler, UT Southwestern

National collaborators
Karin Loré, Department of Medicine, Solna, KI
Mikael Karlsson, MTC, KI
Robert Månsson, Center for Hematology and Regenerative Medicine (HERM)

Funding

We gratefully receive financial support for our research from several organizations, currently from:

Swedish Research Council (Vetenskapsrådet, VR)
International AIDS Vaccine Initiative (IAVI)
Karolinska Institutet (KID medel)
National Institutes of Health (NIH)
European Research Council Advanced Grant
Wenner-Gren Foundation
European Union, H2020
SciLifeLab Bioinformatics Long-term Support
Fondation Dormeur, Vaduz