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Human circulating T follicular helper cells during viral infection and autoimmunity
Human circulating T follicular helper cells during viral infection and autoimmunity
CD4+ T helper cells orchestrate the adaptive immune response. The differentiation of naïve CD4+ T cells into various functionally different subsets of T helper cells ensures the adaptation of the immune response to the invading pathogen. The T helper cell subset that is responsible for B cell help during affinity maturation in the germinal center (GC) reaction is called T follicular helper (Tfh) cells. Therefore, Tfh cells are crucial to develop long-lasting immunity by ensuring the generation of memory B cells and high-affinity antibody-producing plasma cells. Blood-resident Tfh cells, so called circulating Tfh (cTfh) cells, can be used to investigate human Tfh cells instead of lymphoid tissue-resident Tfh cells, which are difficult to assess in humans. Lymphoid tissue-resident Tfh cells and cTfh cells both provide B cell help and share similarities in phenotype and gene expression. cTfh cells can express other CD4+ T cell subset-defining chemokine receptors and can thereby be clustered into different subsets. Although increased cTfh cell frequencies have been connected to better vaccination outcome and new insights into cTfh cell kinetics might improve the understanding of established vaccinations and impact future vaccine design, only few studies investigated cTfh kinetics after vaccination. Most conclusions were drawn from annual influenza vaccinations that allow for investigation of recall responses. Nevertheless, it is difficult to distinguish between the primary and secondary immune response as vaccinees have likely been in contact with influenza virus before vaccination and additionally influenza vaccination can have low efficacy. Therefore, I tracked and characterized cTfh and other blood-resident immune cells by flow cytometry after challenge with a live virus in the context of a vaccination against yellow fever. Yellow fever virus (YFV) is endemic in tropical regions. Yellow fever vaccination elicits a strong, long-lasting immune response with neutralizing antibodies in almost all vaccinees. We were able to show that vaccination with the attenuated yellow fever virus elicited an increased frequency of activated cTfh cells from three days on after vaccination. The peak frequency of activated cTfh cells was detectable 14 days after vaccination. In addition, we observed a shift in the subset composition of cTfh cells during the immune response with cTfh1 cells as the most prevalent subpopulation. Those findings were confirmed by the detection of YFV-specific CD4+ T cells in the blood with major histocompatibility complex (MHC) II tetramers for four known epitopes. Moreover, we found a correlation of frequencies of cTfh1 cells with the strength of the neutralizing antibody response, which might influence future vaccine design. Tfh cells have also been implicated in the pathogenesis of several autoimmune diseases and are for example contained in ectopic lymphoid structures and implicated in the formation of autoantibodies. Multiple sclerosis (MS) often involves ectopic lymphoid structures and oligoclonal bands in the cerebrospinal fluid and multiple studies point to a role of Tfh cells in multiple sclerosis. Yet, cTfh cells and the impact of immunomodulatory drugs are not well investigated in patients with MS. Therefore, I compared blood-resident T and B cell populations of patients with multiple sclerosis, that either received no treatment or different immunomodulatory drugs, with cells derived from healthy donors. Although cTfh cells from MS patients were phenotypically not distinguishable from healthy donors, immunomodulatory treatment with the sphingosine-1-phosphate receptor (S1PR) 1 blocking drug fingolimod resulted in profoundly reduced frequencies of cTfh cells. Additionally, other T cells expressing the Tfh cell hallmark chemokine receptor CXCR5, such as T follicular regulatory cells and CXCR5+CD8+ T cells, were similarly affected. This provides insight into the migratory pattern of cTfh cells as well as a better understanding of the impact of fingolimod on blood-resident lymphocyte populations. In summary, the findings I present in this thesis contribute to a better understanding of circulating Tfh cells after viral challenge and immunomodulation. This might have implications for vaccine design and for the treatment of autoimmune diseases.
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Huber, Johanna Elisabeth
2020
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Huber, Johanna Elisabeth (2020): Human circulating T follicular helper cells during viral infection and autoimmunity. Dissertation, LMU München: Faculty of Medicine
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Abstract

CD4+ T helper cells orchestrate the adaptive immune response. The differentiation of naïve CD4+ T cells into various functionally different subsets of T helper cells ensures the adaptation of the immune response to the invading pathogen. The T helper cell subset that is responsible for B cell help during affinity maturation in the germinal center (GC) reaction is called T follicular helper (Tfh) cells. Therefore, Tfh cells are crucial to develop long-lasting immunity by ensuring the generation of memory B cells and high-affinity antibody-producing plasma cells. Blood-resident Tfh cells, so called circulating Tfh (cTfh) cells, can be used to investigate human Tfh cells instead of lymphoid tissue-resident Tfh cells, which are difficult to assess in humans. Lymphoid tissue-resident Tfh cells and cTfh cells both provide B cell help and share similarities in phenotype and gene expression. cTfh cells can express other CD4+ T cell subset-defining chemokine receptors and can thereby be clustered into different subsets. Although increased cTfh cell frequencies have been connected to better vaccination outcome and new insights into cTfh cell kinetics might improve the understanding of established vaccinations and impact future vaccine design, only few studies investigated cTfh kinetics after vaccination. Most conclusions were drawn from annual influenza vaccinations that allow for investigation of recall responses. Nevertheless, it is difficult to distinguish between the primary and secondary immune response as vaccinees have likely been in contact with influenza virus before vaccination and additionally influenza vaccination can have low efficacy. Therefore, I tracked and characterized cTfh and other blood-resident immune cells by flow cytometry after challenge with a live virus in the context of a vaccination against yellow fever. Yellow fever virus (YFV) is endemic in tropical regions. Yellow fever vaccination elicits a strong, long-lasting immune response with neutralizing antibodies in almost all vaccinees. We were able to show that vaccination with the attenuated yellow fever virus elicited an increased frequency of activated cTfh cells from three days on after vaccination. The peak frequency of activated cTfh cells was detectable 14 days after vaccination. In addition, we observed a shift in the subset composition of cTfh cells during the immune response with cTfh1 cells as the most prevalent subpopulation. Those findings were confirmed by the detection of YFV-specific CD4+ T cells in the blood with major histocompatibility complex (MHC) II tetramers for four known epitopes. Moreover, we found a correlation of frequencies of cTfh1 cells with the strength of the neutralizing antibody response, which might influence future vaccine design. Tfh cells have also been implicated in the pathogenesis of several autoimmune diseases and are for example contained in ectopic lymphoid structures and implicated in the formation of autoantibodies. Multiple sclerosis (MS) often involves ectopic lymphoid structures and oligoclonal bands in the cerebrospinal fluid and multiple studies point to a role of Tfh cells in multiple sclerosis. Yet, cTfh cells and the impact of immunomodulatory drugs are not well investigated in patients with MS. Therefore, I compared blood-resident T and B cell populations of patients with multiple sclerosis, that either received no treatment or different immunomodulatory drugs, with cells derived from healthy donors. Although cTfh cells from MS patients were phenotypically not distinguishable from healthy donors, immunomodulatory treatment with the sphingosine-1-phosphate receptor (S1PR) 1 blocking drug fingolimod resulted in profoundly reduced frequencies of cTfh cells. Additionally, other T cells expressing the Tfh cell hallmark chemokine receptor CXCR5, such as T follicular regulatory cells and CXCR5+CD8+ T cells, were similarly affected. This provides insight into the migratory pattern of cTfh cells as well as a better understanding of the impact of fingolimod on blood-resident lymphocyte populations. In summary, the findings I present in this thesis contribute to a better understanding of circulating Tfh cells after viral challenge and immunomodulation. This might have implications for vaccine design and for the treatment of autoimmune diseases.