Genetic basis for B and T cell recognition and function – Gunilla Karlsson Hedestam Group

Our research focuses on adaptive immune responses and qualitative properties of B- and T-cell repertoires. A specific interest in the group is to understand individual variation in germline V, D and J genes and how this influences antigen-specific responses in the context of infection, vaccination and autoimmunity.

Gunilla Karlsson Hedestam Group 2024

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. In several projects, we define anti-viral 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 and characterization 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

IgDiscover

IgDiscover

The production of individualized genetic profiles of B cell receptor and T cell receptor V, D and J genes is central in many areas of research and for personalized medicine applications. While standard deep sequencing approaches do not achieve necessary coverage to profile these genes, the use of IgDiscover and related technologies, can achieve this. Recent developments of the IgDiscover pipeline include tools for high throughput genotyping and haplotype analysis. Click here to visit IgDiscover.

VDJ Databases

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Publications

Selected publications

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Funding

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Funding

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

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Postal address

Karolinska Institutet
Department of Microbiology, Tumor and Cell Biology
171 77 Stockholm

Visiting address (visitors, couriers, etc.)

Karolinska Institutet
Biomedicum, C7
Solnavägen 9
171 65 Solna

Delivery address (goods, parcels, etc.)

Tomtebodavägen 16
171 65 Solna

Where to find us

Karolinska Institutet, Biomedicum, Solnavägen 9

Research projects

Studies of adaptive immune receptor germline gene variation

Recent results using Next Generation sequencing have revealed significant allelic diversity in the genes encoding the human B and T cell receptors (BCRs/antibodies and TCRs). The production of individualized genetic profiles of adaptive immune receptor genes is therefore of interest, both to aid future personalized vaccination strategies and for diagnostic purposes. While standard deep sequencing approaches do not achieve necessary coverage to create full profiles of these genes, the use of IgDiscover and related technologies, can achieve this.

In this project, we characterize human genetic diversity in adaptive immune receptor genes, focusing initially on BCR and TCR V, D and J genes. These efforts will allow the production of improved genetic databases and an improved understanding of the frequency of different alleles present in different population.

In parallel, we apply similar approaches to characterize adaptive immune receptor genes in several non-human primate species for which genetic databases today are largely lacking.

References

Archaic humans have contributed to large-scale variation in modern human T cell receptor genes.
Corcoran M, Chernyshev M, Mandolesi M, Narang S, Kaduk M, Ye K, Sundling C, Färnert A, Kreslavsky T, Bernhardsson C, Larena M, Jakobsson M, Karlsson Hedestam GB
Immunity 2023 Mar;56(3):635-652.e6

Immunoglobulin germline gene polymorphisms influence the function of SARS-CoV-2 neutralizing antibodies.
Pushparaj P, Nicoletto A, Sheward DJ, Das H, Castro Dopico X, Perez Vidakovics L, Hanke L, Chernyshev M, Narang S, Kim S, Fischbach J, Ekström S, McInerney G, Hällberg BM, Murrell B, Corcoran M, Karlsson Hedestam GB
Immunity 2023 Jan;56(1):193-206.e7

Analysis of IGH allele content in a sample group of rheumatoid arthritis patients demonstrates unrevealed population heterogeneity.
Hardt U, Corcoran MM, Narang S, Malmström V, Padyukov L, Karlsson Hedestam GB
Front Immunol 2023 ;14():1073414

Addressing IGHV Gene Structural Diversity Enhances Immunoglobulin Repertoire Analysis: Lessons From Rhesus Macaque.
Kaduk M, Corcoran M, Karlsson Hedestam GB
Front Immunol 2022 ;13():818440

Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity.
Corcoran MM, Phad GE, Vázquez Bernat , Stahl-Hennig C, Sumida N, Persson MA, Martin M, Karlsson Hedestam GB
Nat Commun 2016 12;7():13642

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, Maisonasse P, Dereuddre-Bosquet N, Murrell B, Karlsson Hedestam GB
Immunity 2021 02;54(2):355-366.e4

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, Karlsson Hedestam GB
Front Immunol 2019 ;10():660

Studies of expressed B cell receptor repertoires

B cell responses are the basis by which most effective anti-viral vaccines provide protection against infection and disease. Vaccines are still lacking for many human pathogens and in other cases they exist, but do not provide sufficiently broad or long-lasting responses.

A robust understanding of B cell biology is needed to develop broadly protective and durable antibody responses.

Comprehensive analyses of B cell clones engaged by a specific antigen during infection or immunization, and analysis of how such responses develop over time, are topics of specific interest. We focus particularly on neutralizing anti-viral antibodies and their targets. Characterization of vaccine-induced monoclonal antibodies combined with analysis of unfractionated polyclonal plasma samples and deep sequencing of antibody repertoires expressed by different B cell populations provide a rich source of information. With improved methods to sort antigen-specific B cell populations by flow cytometry and sequence large numbers of paired heavy and light chains, we can now make rapid progress to identify interesting antibody specificities against a range of targets. Questions we are particularly interested in are how antibody responses mature over time, clonal dynamics of the response, qualitative differences between the peripheral memory B cell compartment and the bone marrow plasma cell repertoire against a given antigen, and if specific germline immunoglobulin alleles are required for certain types of antibody specificities.

References

Vaccination induces HIV broadly neutralizing antibody precursors in humans.
Leggat DJ, Cohen KW, Willis JR, Fulp WJ, deCamp AC, Kalyuzhniy O, Cottrell CA, Menis S, Finak G, Ballweber-Fleming L, Srikanth A, Plyler JR, Schiffner T, Liguori A, Rahaman F, Lombardo A, Philiponis V, Whaley RE, Seese A, Brand J, Ruppel AM, Hoyland W, Yates NL, Williams LD, Greene K, Gao H, Mahoney CR, Corcoran MM, Cagigi A, Taylor A, Brown DM, Ambrozak DR, Sincomb T, Hu X, Tingle R, Georgeson E, Eskandarzadeh S, Alavi N, Lu D, Mullen TM, Kubitz M, Groschel B, Maenza J, Kolokythas O, Khati N, Bethony J, Crotty S, Roederer M, Karlsson Hedestam GB, Tomaras GD, Montefiori D, Diemert D, Koup RA, Laufer DS, McElrath MJ, McDermott AB, Schief WR
Science 2022 Dec;378(6623):eadd6502

VDJ Gene Usage in IgM Repertoires of Rhesus and Cynomolgus Macaques.
Chernyshev M, Kaduk M, Corcoran M, Karlsson Hedestam GB
Front Immunol 2021 ;12():815680

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.
Aljedani SS, Liban TJ, Tran K, Phad G, Singh S, Dubrovskaya V, Pushparaj P, Martinez-Murillo P, Rodarte J, Mileant A, Mangala Prasad V, Kinzelman R, O'Dell S, Mascola JR, Lee KK, Karlsson Hedestam GB, Wyatt RT, Pancera M
PLoS Pathog 2021 Sep;17(9):e1009543

Single-cell and deep sequencing of IgG-switched macaque B cells reveal a diverse Ig repertoire following immunization.
Sundling C, Zhang Z, Phad GE, Sheng Z, Wang Y, Mascola JR, Li Y, Wyatt RT, Shapiro L, Karlsson Hedestam GB
J Immunol 2014 Apr;192(8):3637-44

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, Feng Y, Mascola JR, Wyatt RT, Karlsson Hedestam GB
Sci Transl Med 2012 Jul;4(142):142ra96

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, Sundling C, Li Y, Stanfield RL, Wilson IA, Ward AB, Karlsson Hedestam GB, Wyatt RT
Proc Natl Acad Sci U S A 2014 Feb;111(7):E738-47

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, Phad GE, Vázquez Bernat N, Bale S, Ingale J, Dubrovskaya V, O'Dell S, Pramanik L, Spångberg M, Corcoran M, Loré K, Mascola JR, Wyatt RT, Karlsson Hedestam GB
Immunity 2017 05;46(5):804-817.e7

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, Vázquez Bernat N, Singh S, Dionne G, O'Dell S, Bhullar K, Narang S, Sorini C, Villablanca EJ, Sundling C, Murrell B, Mascola JR, Shapiro L, Pancera M, Martin M, Corcoran M, Wyatt RT, Karlsson Hedestam GB
J Exp Med 2020 02;217(2):

SARS-CoV-2-directed B cell responses and isolation of spike-specific monoclonal antibodies

Antibody responses to SARS-CoV-2 are central for individual and population-level immunity. However, with recently emerged virus variants, responses from prior exposures or vaccination are not fully protective. Seroprevalence studies and detailed antibody mapping studies are key to our understanding of protective immunity.

In this project, we follow antibody levels in the population and assess neutralizing antibody responses against SARS-CoV-2 variants of concern. We also study memory B cell responses in defined cohorts of exposed individuals by using single B cell sorting, isolation of virus-specific monoclonal antibodies and NGS-based bulk BCR repertoire sequencing to of antibody affinity maturation and persistence in the memory B cell compartment.

In collaboration with the Murrell group, we recently characterized a set of highly potent monoclonal antibodies that neutralize Omicron and related variants. In other projects, we investigate the role of VDJ germline gene variation for neutralizing antibody responses against this virus to understand inter-individual variation in the response against SARS-CoV-2.

References

Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages.
Chernyshev M, Sakharkar M, Connor RI, Dugan HL, Sheward DJ, Rappazzo CG, Stålmarck A, Forsell MNE, Wright PF, Corcoran M, Murrell B, Walker LM, Karlsson Hedestam GB
Nat Commun 2023 Apr;14(1):2249

Frequent use of IGHV3-30-3 in SARS-CoV-2 neutralizing antibody responses.
Pushparaj P, Nicoletto A, Dopico XC, Sheward DJ, Kim S, Ekström S, Murrell B, Corcoran M, Karlsson Hedestam GB
Front Virol 2023 Mar;3():1128253

Immunoglobulin germline gene polymorphisms influence the function of SARS-CoV-2 neutralizing antibodies.
Pushparaj P, Nicoletto A, Sheward DJ, Das H, Castro Dopico X, Perez Vidakovics L, Hanke L, Chernyshev M, Narang S, Kim S, Fischbach J, Ekström S, McInerney G, Hällberg BM, Murrell B, Corcoran M, Karlsson Hedestam GB
Immunity 2023 Jan;56(1):193-206.e7

Omicron sublineage BA.2.75.2 exhibits extensive escape from neutralising antibodies.
Sheward DJ, Kim C, Fischbach J, Sato K, Muschiol S, Ehling RA, Björkström NK, Karlsson Hedestam GB, Reddy ST, Albert J, Peacock TP, Murrell B
Lancet Infect Dis 2022 Nov;22(11):1538-1540

Evasion of neutralising antibodies by omicron sublineage BA.2.75.
Sheward DJ, Kim C, Fischbach J, Muschiol S, Ehling RA, Björkström NK, Karlsson Hedestam GB, Reddy ST, Albert J, Peacock TP, Murrell B
Lancet Infect Dis 2022 Oct;22(10):1421-1422

Neutralisation sensitivity of the SARS-CoV-2 omicron (B.1.1.529) variant: a cross-sectional study.
Sheward DJ, Kim C, Ehling RA, Pankow A, Castro Dopico X, Dyrdak R, Martin DP, Reddy ST, Dillner J, Karlsson Hedestam GB, Albert J, Murrell B
Lancet Infect Dis 2022 Jun;22(6):813-820

Probabilistic classification of anti-SARS-CoV-2 antibody responses improves seroprevalence estimates.
Castro Dopico X, Muschiol S, Grinberg NF, Aleman S, Sheward DJ, Hanke L, et al.
Clin Transl Immunology. 2022 Mar 2;11(3):e1379

Beta RBD boost broadens antibody-mediated protection against SARS-CoV-2 variants in animal models.
Sheward DJ, Mandolesi M, Urgard E, Kim C, Hanke L, Perez Vidakovics L, Pankow A, Smith NL, Castro Dopico X, McInerney GM, Coquet JM, Karlsson Hedestam GB, Murrell B
Cell Rep Med 2021 11;2(11):100450

Seropositivity in blood donors and pregnant women during the first year of SARS-CoV-2 transmission in Stockholm, Sweden.
Castro Dopico X, Muschiol S, Christian M, Hanke L, Sheward DJ, Grinberg NF, Rorbach J, Bogdanovic G, Mcinerney GM, Allander T, Wallace C, Murrell B, Albert J, Karlsson Hedestam GB
J Intern Med 2021 09;290(3):666-676

SARS-CoV-2 protein subunit vaccination of mice and rhesus macaques elicits potent and durable neutralizing antibody responses.
Mandolesi M, Sheward DJ, Hanke L, Ma J, Pushparaj P, Perez Vidakovics L, Kim C, Àdori M, Lenart K, Loré K, Castro Dopico X, Coquet JM, McInerney GM, Karlsson Hedestam GB, Murrell B
Cell Rep Med 2021 04;2(4):100252

Resources

IgDiscover

IgDiscover

The computational tool, IgDiscover, allows the production of individualized genetic profiles of adaptive immune receptor V, D and J genes, which is central for many areas of research and personalized medicine applications.

Macaque IG VDJ database

Macaque IG VDJ database

This database incorporates IGHV, IGHJ and IGHD sequences from four subgroups of macaques, namely Indian and Chinese origin Rhesus macaques and Indonesian and Mauritian origin Cynomolgus macaques.

Human TCR VDJ database

Human TCR VDJ database

Population-based human V, D and J germline gene sequences for TRA, TRD, TRB and TRG.

Popular science articles

A better picture of the immune response to COVID-19 

When the corona pandemic was a fact in March 2020, Gunilla Karlsson Hedestam, professor of ­vaccine ­immunology at Karolinska Institutet, already had a good idea of how viruses and anti-viral immune ­responses ­generally behave.

Read the article from 2024 on Erling-Perssons stiftelses webb page

Unik katalog över genvariationer ska ge mer precisa läkemedel

Genom att kartlägga immunsystemets gener på djupet vill Gunilla Karlsson Hedestams forskargrupp öka kunskapen kring det mänskliga immunförsvaret. Syftet är att skapa bättre diagnostik och nya terapier för patienter i hela världen. 

Läs artikeln från 2024 på Knut och Alice Wallenbergs stiftelses webbsida 

New approaches to investigating diversity in adaptive immune receptor genes

Hundreds of genes recombine in a combinatorial manner to make B- and T-cell receptors, which are integral to the adaptive immune system. In ImmuneDiversity, a project funded by an ERC Advanced grant, the group is investigating human inter-individual diversity in B- and T-cell receptors genes to obtain an improved understanding of disease susceptibility, as Professor Gunilla Karlsson Hedestam explains in this article in EU Research, Autumn 2023 vol. (35), pp. 14 -16.

Read the article in EU Research

Stor variation i generna som kodar för människans T-cellsreceptorer

Vår kunskap om människans arvsmassa blir allt större tack vare snabbare och bättre metoder att sekvensera DNA. Ju fler personer vars DNA analyseras desto bättre förstår vi vilka regioner av arvsmassan som uppvisar stor variation mellan olika personer. Professor Gunilla Karlsson Hedestam och hennes grupp på Karolinska Institutet visade nyligen att generna som kodar för T-cellernas antigen-receptorer uppvisar exceptionellt stor variation. Detta kan ha betydelse för att förstå orsaker till immunmedierade sjukdomar, till exempel inom neurologin, skriver författaren i Neurologi i Sverige no 2, 2023.

Läs artikeln i Neurologi i Sverige

Former PhD students

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. Paola is now a senior postdoc evaluating extracellular vesicles immune modulation and translational potential in atopic dermatitis in the Mantel lab in Davos, Switzerland.

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. She is currently a Scientific Project Manager in Immunology at the Janssen Pharmaceutical Companies of Johnson & Johnson in Stockholm.

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. After leaving the lab, she took up a position as a TCR discovery scientist at T-knife Therapeutics in Berlin.

Pradeepa Pushparaj

2023

Opponent: Penny Moore

Pradeepa defended her PhD in May 2023. During her studies, Pradeepa gained deep expertise in techniques used to dissect B cell responses at the clonal level to investigate qualitative features of antibody responses elicited by infection or vaccination. By isolating monoclonal antibodies from antigen-specific memory B cells, and combining this with antibody engineering, functional studies, and lineage tracing in deep-sequenced repertoire data, she investigated questions related to antibody affinity maturation and the development of long-lived memory B cells and plasma cells. In her Immunity paper published in 2023, she applied personalized antibody VDJ genotyping to a cohort of SARS-CoV-2 convalescent individuals and showed that germline-encoded polymorphisms can influence the type of antibody response made, illustrating a functional role for antibody germline gene variation in humans.

Marco Mandolesi

2023

Opponent: Bob Seder

Marco defended his PhD in February 2023. His thesis work covered a broad range of topics in immunology, including individualized typing of human and macaque T- and B-cell receptor germline genes, identification and validation of novel alleles, immunization studies and characterization of elicited adaptive immune responses, isolation of monoclonal antibodies and B cell lineage tracing to follow the evolution of the antibody response. His time as a doctoral student in the lab overlapped with the COVID-19 pandemic and he was able to quickly refocus his efforts to contribute to the understanding of SARS-CoV-2-directed neutralizing antibody responses. He also contributed greatly to a paper on TCR germline gene polymorphisms published in Immunity just before his PhD defense. He is highly skilled in immune repertoire analysis and is currently staying on as a post-doctoral scientist to wrap up projects and help supervise new members of the laboratory.

Co-supervisor

Gunilla Karlsson Hederstam has also been co-supervisor for:

  • 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
  • Sebastian Ols, 2022
  • Uta Hardt, 2022