Regulation of vaccine immunity : from myeloid cell functions to antibody responses
Author: Lin, Ang
Date: 2020-01-17
Location: J3:06, Ulf von Euler, Eugeniavägen 3, Karolinska Universitetssjukhuset Solna
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
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Thesis (5.980Mb)
Abstract
The generation of vaccine-induced protection against infections relies on a well-coordinated network of innate immune responses, adaptive cellular responses, and humoral responses. Sufficient stimulation of the innate immune system by vaccination is critical to subsequently induce effective pathogen-specific T cell and B cell responses. The magnitude, characteristics and functions of the T cell and B cell response will further determine the protective effect of the vaccines. This thesis has investigated aspects of both the early innate immune response as well as the adaptive T cell and B cell response after vaccination. Specifically, the first part focuses on the functions of different innate myeloid cell subsets in regulating vaccine responses. The second part focuses on the antibody responses induced by a new live pertussis vaccine compared to the currently used acellular pertussis vaccine (aPV).
Neutrophils are the major circulating myeloid cells. Heterogeneity and plasticity of neutrophils have received much attention during the past years. In Paper I, we show that neutrophils can present antigens to antigen-specific memory CD4+ T cells. This is dependent on the upregulation of MHC-II and costimulatory molecules on neutrophils which can occur in the presence of antigens and autologous antigen-specific memory CD4+ T cells. Furthermore, we found that neutrophils isolated from lymph nodes draining vaccine injection sites of rhesus macaques can present vaccine antigens to antigen-specific CD4+ T cells. Neutrophils may therefore play a role in the induction and regulation of vaccine-specific T cell responses through antigen presentation.
There have been efforts trying to understand how vaccines induce immune responses but much less is known about immune suppressive regulation. In Paper II, we demonstrate that myeloid-derived suppressor cells (MDSCs), which is a unique population of myeloid cells with suppressive functions particularly on T cells, accumulate transiently after vaccination. We found that monocytic (M)-MDSCs and polymorphonuclear (PMN)-MDSCs are present in rhesus blood and possess inherent suppressive effects on T cells. The frequency of M-MDSCs rapidly and transiently increased in the blood, and these cells infiltrated the injection sites after vaccination. We speculate that MDSCs contribute with an immune-balancing role to prevent excessive immune activation and inflammation upon vaccine exposure.
In Paper III, we evaluated the immune responses in humans receiving the live attenuated Bordetella pertussis vaccine BPZE1 in a clinical trial. A single intranasal immunization of BPZE1 induced well-detectable plasmablasts, activated circulating T follicular helper cells, vaccine-specific Th1-polarized CD4+ T cells, memory B cells and antibodies. In contrast to the antibodies induced by the currently used aPV, BPZE1-induced antibodies showed substantially broader specificities to several B. pertussis antigens, many of which were identified for the first time. The BPZE1-induced antibodies were also more potent in mediating bacterial opsonization to stimulate reactive oxygen species production in neutrophils, which further led to enhanced bactericidal function. Collectively, these studies help in the understanding of how myeloid cells dictate immune responses and how the quality and specificities of antibody responses can be influenced by different pertussis vaccine platforms. This information will ultimately aid in the development of better future vaccines.
Neutrophils are the major circulating myeloid cells. Heterogeneity and plasticity of neutrophils have received much attention during the past years. In Paper I, we show that neutrophils can present antigens to antigen-specific memory CD4+ T cells. This is dependent on the upregulation of MHC-II and costimulatory molecules on neutrophils which can occur in the presence of antigens and autologous antigen-specific memory CD4+ T cells. Furthermore, we found that neutrophils isolated from lymph nodes draining vaccine injection sites of rhesus macaques can present vaccine antigens to antigen-specific CD4+ T cells. Neutrophils may therefore play a role in the induction and regulation of vaccine-specific T cell responses through antigen presentation.
There have been efforts trying to understand how vaccines induce immune responses but much less is known about immune suppressive regulation. In Paper II, we demonstrate that myeloid-derived suppressor cells (MDSCs), which is a unique population of myeloid cells with suppressive functions particularly on T cells, accumulate transiently after vaccination. We found that monocytic (M)-MDSCs and polymorphonuclear (PMN)-MDSCs are present in rhesus blood and possess inherent suppressive effects on T cells. The frequency of M-MDSCs rapidly and transiently increased in the blood, and these cells infiltrated the injection sites after vaccination. We speculate that MDSCs contribute with an immune-balancing role to prevent excessive immune activation and inflammation upon vaccine exposure.
In Paper III, we evaluated the immune responses in humans receiving the live attenuated Bordetella pertussis vaccine BPZE1 in a clinical trial. A single intranasal immunization of BPZE1 induced well-detectable plasmablasts, activated circulating T follicular helper cells, vaccine-specific Th1-polarized CD4+ T cells, memory B cells and antibodies. In contrast to the antibodies induced by the currently used aPV, BPZE1-induced antibodies showed substantially broader specificities to several B. pertussis antigens, many of which were identified for the first time. The BPZE1-induced antibodies were also more potent in mediating bacterial opsonization to stimulate reactive oxygen species production in neutrophils, which further led to enhanced bactericidal function. Collectively, these studies help in the understanding of how myeloid cells dictate immune responses and how the quality and specificities of antibody responses can be influenced by different pertussis vaccine platforms. This information will ultimately aid in the development of better future vaccines.
List of papers:
I. Maria Vono, Ang Lin, Anna Norrby-Teglund, Richard A. Koup, Frank Liang, and Karin Loré. Neutrophils acquire the capacity for antigen presentation to memory CD4+ T cells in vitro and ex vivo. Blood. 2017 Apr 6;129(14):1991-2001.
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II. Ang Lin, Frank Liang, Elizabeth A. Thompson, Maria Vono, Sebastian Ols, Gustaf Lindgren, Kimberly Hassett, Hugh Salter, Giuseppe Ciaramella, and Karin Loré. Rhesus macaque myeloid-derived suppressor cells demonstrate T cell inhibitory functions a000418271200027nd are transiently increased after vaccination. The Journal of Immunology. 2018 Jan 1;200(1):286-294.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ang Lin, Danijela Apostolovic, Maja Jahnmatz, Frank Liang, Sebastian Ols, Teghesti Tecleab, Chenyan Wu, Marianne van Hage, Ken Solovay, Keith Rubin, Camille Locht, Rigmor Thorstensson, Marcel Thalen, and Karin Loré. The live attenuated Bordetella pertussis vaccine BPZE1 induces a Th1-polarized broad antibody response in humans. [Manuscript]
I. Maria Vono, Ang Lin, Anna Norrby-Teglund, Richard A. Koup, Frank Liang, and Karin Loré. Neutrophils acquire the capacity for antigen presentation to memory CD4+ T cells in vitro and ex vivo. Blood. 2017 Apr 6;129(14):1991-2001.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ang Lin, Frank Liang, Elizabeth A. Thompson, Maria Vono, Sebastian Ols, Gustaf Lindgren, Kimberly Hassett, Hugh Salter, Giuseppe Ciaramella, and Karin Loré. Rhesus macaque myeloid-derived suppressor cells demonstrate T cell inhibitory functions a000418271200027nd are transiently increased after vaccination. The Journal of Immunology. 2018 Jan 1;200(1):286-294.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ang Lin, Danijela Apostolovic, Maja Jahnmatz, Frank Liang, Sebastian Ols, Teghesti Tecleab, Chenyan Wu, Marianne van Hage, Ken Solovay, Keith Rubin, Camille Locht, Rigmor Thorstensson, Marcel Thalen, and Karin Loré. The live attenuated Bordetella pertussis vaccine BPZE1 induces a Th1-polarized broad antibody response in humans. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Loré, Karin
Co-supervisor: Norrby-Teglund, Anna; Seder, Robert
Issue date: 2019-12-05
Rights:
Publication year: 2019
ISBN: 978-91-7831-594-9
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