Gunilla Karlsson Hedestam Group
Our research focuses on the function of B lymphocytes and qualitative properties of antibody repertoires. A specific interest in the group is to understand individual variation in antibody germline (VDJ) genes and how this influences the elicitation of antigen-specific B cell responses.
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 highly detailed information about polymorphisms in these genes, allowing us to investigate how the VDJ germline allele content influences the establishment of antigen-specific responses.
IgDiscover
Access a computational tool that allows i) the generation of individualized germline immunoglobulin gene databases and ii) analysis of expressed antibody repertoires.
VDJ Databases
The latest set of VDJ alleles reported in Vázquez Bernat et al. is available for download and assignments at http://kimdb.gkhlab.se.
Projects
Studies of adaptive immune receptor germline genes
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
Rhesus and cynomolgus macaque immunoglobulin heavy-chain genotyping yields comprehensive databases of germline VDJ alleles.
Vázquez Bernat N, Corcoran M, Nowak I, Kaduk M, Castro Dopico X, Narang S, et al
Immunity 2021 Jan;():
VRC34-Antibody Lineage Development Reveals How a Required Rare Mutation Shapes the Maturation of a Broad HIV-Neutralizing Lineage.
Shen CH, DeKosky BJ, Guo Y, Xu K, Gu Y, Kilam D, et al
Cell Host Microbe 2020 04;27(4):531-543.e6
Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses.
Phad GE, Pushparaj P, Tran K, Dubrovskaya V, Àdori M, Martinez-Murillo P, et al
J. Exp. Med. 2020 Feb;217(2):
Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability.
Dubrovskaya V, Tran K, Ozorowski G, Guenaga J, Wilson R, Bale S, et al
Immunity 2019 11;51(5):915-929.e7
High-Quality Library Preparation for NGS-Based Immunoglobulin Germline Gene Inference and Repertoire Expression Analysis.
Vázquez Bernat N, Corcoran M, Hardt U, Kaduk M, Phad GE, Martin M, et al
Front Immunol 2019 ;10():660
Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.
Kong R, Duan H, Sheng Z, Xu K, Acharya P, Chen X, et al
Cell 2019 Jul;178(3):567-584.e19
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
Group Members
Associated Researchers
Uta Hardt
Clinical assistantAlumni
Ph.D. students (Name and year of graduation)
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. After several years as a productive member of the Nussenzweig laboratory, she is now back at KI to establish her own research group.
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 is currently a post-doctoral fellow in the laboratory of Antonio Lanzavecchia in Switzerland
Néstor Vazquez Bernat, 2019
Opponent: Scott Boyd
Néstor defended his PhD in December 2019 with a thesis focusing on antibody repertoire sequencing and germline gene identification in humans and macaques. He worked closely with his co-supervisor Martin Corcoran to optimize protocols for IgM library production for germline inference and with methods to validate novel alleles identified with the IgDiscover software. His recent paper in Immunity describes a comprehensive database of rhesus and cynomolgus macaque antibody germline alleles, now publicly available (see above). Néstor is currently working with immune repertoire sequencing at ENPICOM in the Netherlands.
Sharesta Khoenkhoen, 2020
Opponent: David Tarlinton
Sharesta defended her PhD thesis in August 2020. During her doctoral studies, Sharesta studied B cell defects in mice lacking an NFkB regulator, IKBNS. The most striking phenotype of IKBNS-deficient mice is that they fail to develop B-1 cells while follicular B cells (FoB cells) develop and are present at normal frequencies. Sharesta demonstrated that while FoB cells present in IKBNS-deficient mice, they are dysfunctional in their ability to differentiate into plasma cells. Sharesta investigated key steps in this process to pinpoint the defect and she is currently staying on in the lab to finish these studies before heading to Berlin for a post-doc position later this year.
Co-supervisor:
Cornelia Gujer, 2011
Kai Eng, 2012
Lina Josefsson, 2013
Marc Panas, 2014
Lotta Pramanik Sollerkvist, 2014
Faezzah Baharom 2016
Katrin Habir 2018
Julian Stark 2020
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
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
SciLifeLab Bioinformatics Long-term Support
Fondation Dormeur, Vaduz
Visiting Address
Department of Microbiology, Tumor and Cell Biology,
Biomedicum, Block 7C
Solnavägen 9
171 65 Solna
Stockholm,
Sweden