The role of cytohesins in the regulation of immune responses
The role of cytohesins in the regulation of immune responses
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DissertationPrüfungsdatum
21.01.2020Datum der Veröffentlichung
17.02.2020Erstgutachter
Garbi, NatalioZweitgutachter
Kolanus, WaldemarMetadaten
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Inhalt
Cytohesins are guanine nucleotide exchange factors for adenosine diphosphate ribosylation factor (Arf) proteins and promote the switch of Arfs to the active GTP-bound form. Cytohesins have been shown in different in vitro settings to affect cell motility, cell adhesion and chemotaxis of various leukocytes, which are fundamental processes necessary for efficient innate and adaptive immune responses. Furthermore, due to their engagement in phagocytic processes, cytohesins are also targeted by different pathogens during bacterial invasion to evade the immune responses and to exert their full pathogenicity. However, all the evidence for the regulation of immunity by cytohesins has derived from in vitro studies. The primary impact(s) of different cytohesins on the regulation and coordination of the immune responses in the control of infection in vivo has not been elucidated.
The aim of this PhD thesis was to investigate the in vivo function of cytohesin-1, cytohesin-2 and cytohesin-3 in the complex immune responses and in pathogenesis by using acute infection with the respiratory pathogens Legionella pneumophila and influenza A virus in knockout mice. L. pneumophila is a Gram-negative bacteria and the causative agent for Legionnaires’ Disease, and influenza A virus causes ”flu”, which occurs in seasonal and pandemic outbreaks.
These studies revealed that cytohesin-1 promotes T cell responses in both bacterial and viral respiratory infections. Moreover, in influenza A infection, cytohesin-1 deficiency hampered development of cognate T cells and their response to cognate antigens. Cytohesin-1 was demonstrated experimentally to be involved in the initial activation phase of naïve T cells and was required for optimal metabolic switching of T cells following activation. Lack of cytohesin-1 impaired the differentiation of distinct helper T cells, but also different memory and effector cell types.
Myeloid-specific deletion of cytohesin-2 transiently impaired cDC recruitment in the course of bacterial infection highlighting a potential intrinsic role in cDC biology. However, this did not have major effects on the overall phenotype of L. pneumophila or influenza A infection.
Interestingly, cytohesin-3 had an opposing role on T cells compared to cytohesin-1 and suppressed T cell immune responses in both L. pneumophila and influenza A infection. Increased infiltration of several different T cell subpopulations to the site of infection and increased acquisition of antigen-specific responses was observed in cytohesin-3 deficient mice. Furthermore, cytohesin-3 deficient T cells were more reactive to cognate stimulation leading to enhanced cellular immune responses. Additionally, recovery from L. pneumophila infection was delayed in cytohesin-3 deficient mice, suggesting that cytohesin-3 is important for preventing overactivation of T cells and any resulting inflammatory disease.
In conclusion, this PhD thesis provided for the first time a broad in vivo examination of the role(s) of different cytohesins in the immune responses to pulmonary infections. Although minor roles were found for cytohesins in regulating innate immune responses, the primary role(s) of cytohesin-1 and cytohesin-3 appear to lie in the regulation of T cells. Cytohesin-1 promotes T cell responses potentially by providing the optimal (signalling) threshold and by supporting the bioenergetic adaptation following T cell activation, while cytohesin-3 may suppress T cell responses by acting as an immune checkpoint.
The aim of this PhD thesis was to investigate the in vivo function of cytohesin-1, cytohesin-2 and cytohesin-3 in the complex immune responses and in pathogenesis by using acute infection with the respiratory pathogens Legionella pneumophila and influenza A virus in knockout mice. L. pneumophila is a Gram-negative bacteria and the causative agent for Legionnaires’ Disease, and influenza A virus causes ”flu”, which occurs in seasonal and pandemic outbreaks.
These studies revealed that cytohesin-1 promotes T cell responses in both bacterial and viral respiratory infections. Moreover, in influenza A infection, cytohesin-1 deficiency hampered development of cognate T cells and their response to cognate antigens. Cytohesin-1 was demonstrated experimentally to be involved in the initial activation phase of naïve T cells and was required for optimal metabolic switching of T cells following activation. Lack of cytohesin-1 impaired the differentiation of distinct helper T cells, but also different memory and effector cell types.
Myeloid-specific deletion of cytohesin-2 transiently impaired cDC recruitment in the course of bacterial infection highlighting a potential intrinsic role in cDC biology. However, this did not have major effects on the overall phenotype of L. pneumophila or influenza A infection.
Interestingly, cytohesin-3 had an opposing role on T cells compared to cytohesin-1 and suppressed T cell immune responses in both L. pneumophila and influenza A infection. Increased infiltration of several different T cell subpopulations to the site of infection and increased acquisition of antigen-specific responses was observed in cytohesin-3 deficient mice. Furthermore, cytohesin-3 deficient T cells were more reactive to cognate stimulation leading to enhanced cellular immune responses. Additionally, recovery from L. pneumophila infection was delayed in cytohesin-3 deficient mice, suggesting that cytohesin-3 is important for preventing overactivation of T cells and any resulting inflammatory disease.
In conclusion, this PhD thesis provided for the first time a broad in vivo examination of the role(s) of different cytohesins in the immune responses to pulmonary infections. Although minor roles were found for cytohesins in regulating innate immune responses, the primary role(s) of cytohesin-1 and cytohesin-3 appear to lie in the regulation of T cells. Cytohesin-1 promotes T cell responses potentially by providing the optimal (signalling) threshold and by supporting the bioenergetic adaptation following T cell activation, while cytohesin-3 may suppress T cell responses by acting as an immune checkpoint.
Schlagwörter
Cytohesin, Legionella, Influenza, T cells
Klassifikation (DDC)
500 NaturwissenschaftenSolomatina, Anastasia: The role of cytohesins in the regulation of immune responses. - Bonn, 2020. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Melbourne.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-57402
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-57402
@phdthesis{handle:20.500.11811/8328,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-57402,
author = {{Anastasia Solomatina}},
title = {The role of cytohesins in the regulation of immune responses},
school = {{Rheinische Friedrich-Wilhelms-Universität Bonn} and {University of Melbourne}},
year = 2020,
month = feb,
note = {Cytohesins are guanine nucleotide exchange factors for adenosine diphosphate ribosylation factor (Arf) proteins and promote the switch of Arfs to the active GTP-bound form. Cytohesins have been shown in different in vitro settings to affect cell motility, cell adhesion and chemotaxis of various leukocytes, which are fundamental processes necessary for efficient innate and adaptive immune responses. Furthermore, due to their engagement in phagocytic processes, cytohesins are also targeted by different pathogens during bacterial invasion to evade the immune responses and to exert their full pathogenicity. However, all the evidence for the regulation of immunity by cytohesins has derived from in vitro studies. The primary impact(s) of different cytohesins on the regulation and coordination of the immune responses in the control of infection in vivo has not been elucidated.
The aim of this PhD thesis was to investigate the in vivo function of cytohesin-1, cytohesin-2 and cytohesin-3 in the complex immune responses and in pathogenesis by using acute infection with the respiratory pathogens Legionella pneumophila and influenza A virus in knockout mice. L. pneumophila is a Gram-negative bacteria and the causative agent for Legionnaires’ Disease, and influenza A virus causes ”flu”, which occurs in seasonal and pandemic outbreaks.
These studies revealed that cytohesin-1 promotes T cell responses in both bacterial and viral respiratory infections. Moreover, in influenza A infection, cytohesin-1 deficiency hampered development of cognate T cells and their response to cognate antigens. Cytohesin-1 was demonstrated experimentally to be involved in the initial activation phase of naïve T cells and was required for optimal metabolic switching of T cells following activation. Lack of cytohesin-1 impaired the differentiation of distinct helper T cells, but also different memory and effector cell types.
Myeloid-specific deletion of cytohesin-2 transiently impaired cDC recruitment in the course of bacterial infection highlighting a potential intrinsic role in cDC biology. However, this did not have major effects on the overall phenotype of L. pneumophila or influenza A infection.
Interestingly, cytohesin-3 had an opposing role on T cells compared to cytohesin-1 and suppressed T cell immune responses in both L. pneumophila and influenza A infection. Increased infiltration of several different T cell subpopulations to the site of infection and increased acquisition of antigen-specific responses was observed in cytohesin-3 deficient mice. Furthermore, cytohesin-3 deficient T cells were more reactive to cognate stimulation leading to enhanced cellular immune responses. Additionally, recovery from L. pneumophila infection was delayed in cytohesin-3 deficient mice, suggesting that cytohesin-3 is important for preventing overactivation of T cells and any resulting inflammatory disease.
In conclusion, this PhD thesis provided for the first time a broad in vivo examination of the role(s) of different cytohesins in the immune responses to pulmonary infections. Although minor roles were found for cytohesins in regulating innate immune responses, the primary role(s) of cytohesin-1 and cytohesin-3 appear to lie in the regulation of T cells. Cytohesin-1 promotes T cell responses potentially by providing the optimal (signalling) threshold and by supporting the bioenergetic adaptation following T cell activation, while cytohesin-3 may suppress T cell responses by acting as an immune checkpoint.},
url = {https://hdl.handle.net/20.500.11811/8328}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-57402,
author = {{Anastasia Solomatina}},
title = {The role of cytohesins in the regulation of immune responses},
school = {{Rheinische Friedrich-Wilhelms-Universität Bonn} and {University of Melbourne}},
year = 2020,
month = feb,
note = {Cytohesins are guanine nucleotide exchange factors for adenosine diphosphate ribosylation factor (Arf) proteins and promote the switch of Arfs to the active GTP-bound form. Cytohesins have been shown in different in vitro settings to affect cell motility, cell adhesion and chemotaxis of various leukocytes, which are fundamental processes necessary for efficient innate and adaptive immune responses. Furthermore, due to their engagement in phagocytic processes, cytohesins are also targeted by different pathogens during bacterial invasion to evade the immune responses and to exert their full pathogenicity. However, all the evidence for the regulation of immunity by cytohesins has derived from in vitro studies. The primary impact(s) of different cytohesins on the regulation and coordination of the immune responses in the control of infection in vivo has not been elucidated.
The aim of this PhD thesis was to investigate the in vivo function of cytohesin-1, cytohesin-2 and cytohesin-3 in the complex immune responses and in pathogenesis by using acute infection with the respiratory pathogens Legionella pneumophila and influenza A virus in knockout mice. L. pneumophila is a Gram-negative bacteria and the causative agent for Legionnaires’ Disease, and influenza A virus causes ”flu”, which occurs in seasonal and pandemic outbreaks.
These studies revealed that cytohesin-1 promotes T cell responses in both bacterial and viral respiratory infections. Moreover, in influenza A infection, cytohesin-1 deficiency hampered development of cognate T cells and their response to cognate antigens. Cytohesin-1 was demonstrated experimentally to be involved in the initial activation phase of naïve T cells and was required for optimal metabolic switching of T cells following activation. Lack of cytohesin-1 impaired the differentiation of distinct helper T cells, but also different memory and effector cell types.
Myeloid-specific deletion of cytohesin-2 transiently impaired cDC recruitment in the course of bacterial infection highlighting a potential intrinsic role in cDC biology. However, this did not have major effects on the overall phenotype of L. pneumophila or influenza A infection.
Interestingly, cytohesin-3 had an opposing role on T cells compared to cytohesin-1 and suppressed T cell immune responses in both L. pneumophila and influenza A infection. Increased infiltration of several different T cell subpopulations to the site of infection and increased acquisition of antigen-specific responses was observed in cytohesin-3 deficient mice. Furthermore, cytohesin-3 deficient T cells were more reactive to cognate stimulation leading to enhanced cellular immune responses. Additionally, recovery from L. pneumophila infection was delayed in cytohesin-3 deficient mice, suggesting that cytohesin-3 is important for preventing overactivation of T cells and any resulting inflammatory disease.
In conclusion, this PhD thesis provided for the first time a broad in vivo examination of the role(s) of different cytohesins in the immune responses to pulmonary infections. Although minor roles were found for cytohesins in regulating innate immune responses, the primary role(s) of cytohesin-1 and cytohesin-3 appear to lie in the regulation of T cells. Cytohesin-1 promotes T cell responses potentially by providing the optimal (signalling) threshold and by supporting the bioenergetic adaptation following T cell activation, while cytohesin-3 may suppress T cell responses by acting as an immune checkpoint.},
url = {https://hdl.handle.net/20.500.11811/8328}
}
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