Gunilla Karlsson Hedestam Group
Our immune systems are actively monitoring our tissues for signs of infection to mount rapid primary responses and to establish antigen-specific recall responses. We are interested in understanding how early interactions between pathogens and immune cells influence the development of B cell responses and how such responses evolve over time. Antibodies, produced by B cells after their differentiation into plasma cells, are responsible for the protective effect mediated by most existing vaccines. A major focus in the group is to investigate B cell responses elicited by immunization, in particular by protein-based immunogens such as the HIV-1 envelope glycoproteins (Env). The aim of this work is to establish a basic understanding of how complex protein antigens are handled by the immune system and to identify strategies to direct responses to conserved neutralizing antibody targets. In several projects, we study properties of vaccine-induced B cell responses at the clonal level by single-cell sorting memory B cells and plasma cells, for sequence analysis of antibody V(D)J transcripts and for isolation of pathogen-specific monoclonal antibodies. We further apply next generation sequencing to analyze antibody repertoires from bulk B cells for a detailed examination of the level of affinity maturation of specific antibody lineages and to study their recruitment into specific immune compartments. These studies provide new and detailed information about the establishment of long-lived immunity in response to immunization.
We are also engaged in an ENU screen to identify genes not previously known to play a role in the response to immunization. This screen has generated a number of mouse strains with point mutations that perturb B cell function, several of which are mapped. Some of these strains are now undergoing mechanistic investigations. Recently, we focused our attention on a mouse strain that displays defects in both T-dependent and T-independent B cell responses due to a point mutation in a regulator of the NF-kB pathway. This work has led us to define steps in the differentiation of hematopoietic cells of importance for the development of innate-like B cells, which provide first-line defense against a number of infections. Through this work we are building up a comprehensive understanding of the capacity of the humoral immune system to respond to infections that will facilitate the development of new approaches for vaccination and immunotherapy. The research projects in the group are described in more detail under the headings below.
Affiliated project leaders
B cell repertoire analysis and antibody isolation from single cells following immunization
Diverse antibody genetic and recognition properties revealed following HIV-1 envelope glycoprotein immunization.
J. Immunol. 2015 Jun;194(12):5903-14
Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants.
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.
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.
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.
Proc. Natl. Acad. Sci. U.S.A. 2014 Feb;111(7):E738-47
Independent expansion of epitope-specific plasma cell responses upon HIV-1 envelope glycoprotein immunization.
J. Immunol. 2013 Jul;191(1):44-51
Isolation of antibody V(D)J sequences from single cell sorted rhesus macaque B cells.
J. Immunol. Methods 2012 Dec;386(1-2):85-93
High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site.
Sci Transl Med 2012 Jul;4(142):142ra96
BLyS-mediated modulation of naive B cell subsets impacts HIV Env-induced antibody responses.
J. Immunol. 2012 Jun;188(12):6018-26
Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates.
J. Exp. Med. 2010 Aug;207(9):2003-17
The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus.
Nat. Rev. Microbiol. 2008 Feb;6(2):143-55
Mechanistic studies of mice with defects in humoral immune responses
NF-κB signaling in B-1 cell development
Pedersen G., Àdori A. and Karlsson Hedestam, G.B.
Annals of the New York Academy of Sciences. (2015) In press
Real-time resolution of point mutations that cause phenovariance in mice.
Proc. Natl. Acad. Sci. U.S.A. 2015 Feb;112(5):E440-9
MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses.
Science 2014 Dec;346(6216):1486-92
Slc15a4 function is required for intact class switch recombination to IgG2c in response to TLR9 stimulation.
Immunol. Cell Biol. 2015 Feb;93(2):136-46
B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS.
Proc. Natl. Acad. Sci. U.S.A. 2014 Sep;111(39):E4119-26
A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity.
Proc. Natl. Acad. Sci. U.S.A. 2012 Jul;109(31):12286-93
A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha.
Proc. Natl. Acad. Sci. U.S.A. 2010 Feb;107(7):3046-51
Jonathan Coquet Project:
PhD students (name and year of graduation)
Åsa Hidmark, 2007
Mattias Forsell, 2008
Pia Dosenovic, 2012
Christopher Sundling, 2012,
Cornelia Gujer, 2011
Kai Eng, 2012
Lina Josefsson, 2013
Lotta Pramanik Sollerkvist, 2014
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
John Mascola, Vaccine Research Center, NIH
Richard Wyatt, The Scripps Research Center
Larry Shapiro, Columbia University
Michael Cancro, University of Pennsylvania
Margaret Ackerman, Dartmouth College
Bruce Beutler, UT Southwestern
Roberto Cattaneo, Mayo Clinic
Michel Nussenzweig, Rockefeller University
Joe Sodroski/Navid Madani, Harvard Medical School
Joan Yuan, Lund University
Robin Löving/Henrik Garoff, Dept. of Biosciences and Nutrition, KI
Karin Loré, CIM, KI
Mikael Karlsson, MTC, KI
Stephen Malin, Dept. of Medicine, KI
Pär Nordlund, MBB
Mats Persson, Department of Clinical Neuroscience, KI
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)
Stiftelsen Clas Groschinskys Minnesfond
The Swedish Society of Medicine
Agency for Science, Technology and Research (A*STAR)
Bill and Melinda Gates Foundation
National Institutes of Health (NIH)
KI-Mayo Clinic Collaborative Grants
David och Astrid Hageléns stiftelse
Department of Microbiology, Tumor and Cell Biology Karolinska Institutet P.O. Box 280 Nobels väg 16 SE-171 77 Stockholm, Sweden