Gunilla Karlsson Hedestam
We work on anti-viral immune responses and immunogenetics. A central question is how immunoglobulin germline gene variation shapes the naïve B cell pool and how this affects functional responses.
I received my BSc from Uppsala University in 1990 and my PhD (DPhil) from the University of Oxford in 1993. Between 1994 and 1998, I was a post-doctoral fellow at the Dana-Farber Cancer Institute at Harvard Medical School in Boston, after which I worked in the Biotech sector for 3 years. I then returned to Sweden and Karolinska Institutet where I became an Associate Professor in 2004 and a tenured Professor in 2012. I currently hold a Distinguished Professor grant from the Swedish Research Council, grants from the NIH and the EU H2020 program, as well as an ERC Advanced grant. My group currently consists of the following members: Martin Corcoran, senior research specialist, Monika Ádori, senior research specialist, Xaquin Dopico Castro, research specialist, Mateusz Kaduk, research specialist/computational, Marco Mandolesi, post-doc, Pradeepa Pushparaj, PhD student, Sanjana Narang PhD student, Mark Chernyshev, PhD student, Fabian Schleich, PhD student, Andrea Nicoletti, research assistant, and Martina Löfstedt-Jalava, part-time coordinator. In addition, Assistant Professor Ben Murrell and his group is affiliated to my group.
Infection Immunology and Immunogenetics
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. 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 antigen-specific immune responses and about how outbred species differ in their antibody VDJ germline gene segments and hence the formation of naive B cell repertoires.
Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages - PubMed (nih.gov) M. Chernyshev, M. Sakharkar, R.I. Connor, H.L. Dugan, G. Rappazzo, P.F. Wright, et al. “Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages” Nature Communications, 14(1):2249
Archaic humans have contributed to large-scale variation in modern human T cell receptor genes - PubMed (nih.gov) M. Corcoran, M. Chernyshev, M. Mandolesi, M. Kaduk, S. Narang, Kewei Ye et al. “Archaic humans have contributed to large-scale variation in modern human T cell receptor genes” (2023), Immunity 56(3):635-652.e6
Immunoglobulin germline gene polymorphisms influence the function of SARS-CoV-2 neutralizing antibodies - PubMed (nih.gov) P. Pushparaj, A. Nicoletto, D. Sheward, H. Das, X. Castro Dopico, L. Perez Vidakovics, et al. “Influence of immunoglobulin genotype on the elicitation of SARS CoV-2 neutralizing antibodies” (2023) Immunity 56; 193-206.e7
Vaccination induces HIV broadly neutralizing antibody precursors in humans - PubMed (nih.gov) D.J. Leggat, K.W. Cohen, J.R. Willis, W.J. Fulp, A.C. deCamp, O. Kalyuzhniy, et al. “Efficient vaccine priming of HIV broadly neutralizing antibody precursor B cells in humans” (2022) Science, 378; add6502
Co-immunization with hemagglutinin stem immunogens elicits cross-group neutralizing antibodies and broad protection against influenza A viruses - PubMed (nih.gov) S. M. Moin, J. C. Boyington, S. Boyoglu-Barnum, R. A. Gillespie, G. Cerutti, C. Sao-Fong, et al. “Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses” (2022) Immunity 55; 2405-2418
Neutralisation sensitivity of the SARS-CoV-2 omicron (B.1.1.529) variant: a cross-sectional study - PubMed (nih.gov) D.J. Sheward, C. Kim, R.A. Ehling, A. Pankow, X. Castro Dopico, R. Dyrdak, et al. “Assessing the neutralization sensitivity of SARS-CoV-1 B.1.1.529 (Omicron): a cross-sectional study” (2022) Lancet Infectious Diseases, S1473-3099(22)00129-3
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 Feb 9;54(2):355-366
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 MM, Phad GE, Vázquez Bernat , Stahl-Hennig C, Sumida N, Persson MA, et al. Nat Commun 2016 12;7():13642
B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS - PubMed (nih.gov) Pedersen GK, Àdori M, Khoenkhoen S, Dosenovic P, Beutler B, Karlsson Hedestam GB. Proc. Natl. Acad. Sci. U.S.A. 2014 Sep;111(39):E4119-26
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 GE, 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 GE, Sheng Z, Wang Y, Mascola JR, 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 CN, Pirie E, Dosenovic P, McInerney GM, 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 MN, O'Dell S, Feng Y, Chakrabarti B, Rao SS, 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 GB, Fouchier RA, Phogat S, Burton DR, Sodroski J, Wyatt RT. Nature Rev. Microbiol. 2008 Feb;6(2):143-55