Deciphering cholinergic signaling in CD8+ T cells during acute and chronic viral infection
Deciphering cholinergic signaling in CD8+ T cells during acute and chronic viral infection
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Date of Embargo
15.04.2028Type of Scholarly Publication
DissertationDate of Exam
06.03.2026Date of Publication
02.04.2026Advisor
Abdullah, ZeinabCo-Referee
Utzschneider, DanielMetadata
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Abstract
Acetylcholine is a neurotransmitter of the central and parasympathetic nervous system but can also be produced by immune cells, such as B cell and CD4 T cells. CD8 T cells play an important role in the defense against viral infections and tumor. Here, we deciphered a potential role of cholinergic signaling in effector and memory CD8 T cells during acute viral infection as well as precursor exhausted and exhausted CD8 T cells during chronic viral infection.
In our work, we showed that CD8 T cells express choline acetyltransferase (ChAT), the enzyme that catalyzes the production on acetylcholine, in a T cell receptor-dependent manner. Only antigen-experienced but not naive CD8 T cells can produce acetylcholine. During acute viral infection, ChAT expression peeks during effector phase and decreases dramatically once the virus is cleared. It is partially maintained in memory CD8 T cells. Intriguingly, even though during chronic viral infection, CD8 T cells encounter higher viral load and prolonged antigen-exposure, ChAT expression decreases with progressing T cell exhaustion, indicating an involvement of additional regulatory mechanisms.
Using specific KO mice, we demonstrated that T cell-derived ACh is redundant for effector CD8 T cell differentiation but drives T cell exhaustion. Notably, CD62L+ precursor exhausted CD8 T cells as well as conventional dendritic cells type I were increased in the lymph nodes in T cell-specific ChAT KO mice. In line with that, we showed that long term, the ratio of precursor exhausted to exhausted CD8 T cells was increased, indicating reduced T cell exhaustion.
Lastly, we showed that CD8 T cells express the α7 nicotinic receptor. Deletion of a7 nicotinic receptor in virus-specific CD8 T cells impaired the differentiation of short-lived effector cells during acute infection. Strikingly, α nicotinic receptor is crucial for the maintenance of exhausted CD8 T cells as deletion of α nicotinic receptor in CD8 T cells resulted in a loss of exhausted CD8 T cells by day 21 post infection.
Overall, our work suggests a complex role of cholinergic signaling that can both boost and limit CD8 dysfunction during chronic viral infection but has less impact on functional CD8 T cell differentiation during acute viral infection.
In our work, we showed that CD8 T cells express choline acetyltransferase (ChAT), the enzyme that catalyzes the production on acetylcholine, in a T cell receptor-dependent manner. Only antigen-experienced but not naive CD8 T cells can produce acetylcholine. During acute viral infection, ChAT expression peeks during effector phase and decreases dramatically once the virus is cleared. It is partially maintained in memory CD8 T cells. Intriguingly, even though during chronic viral infection, CD8 T cells encounter higher viral load and prolonged antigen-exposure, ChAT expression decreases with progressing T cell exhaustion, indicating an involvement of additional regulatory mechanisms.
Using specific KO mice, we demonstrated that T cell-derived ACh is redundant for effector CD8 T cell differentiation but drives T cell exhaustion. Notably, CD62L+ precursor exhausted CD8 T cells as well as conventional dendritic cells type I were increased in the lymph nodes in T cell-specific ChAT KO mice. In line with that, we showed that long term, the ratio of precursor exhausted to exhausted CD8 T cells was increased, indicating reduced T cell exhaustion.
Lastly, we showed that CD8 T cells express the α7 nicotinic receptor. Deletion of a7 nicotinic receptor in virus-specific CD8 T cells impaired the differentiation of short-lived effector cells during acute infection. Strikingly, α nicotinic receptor is crucial for the maintenance of exhausted CD8 T cells as deletion of α nicotinic receptor in CD8 T cells resulted in a loss of exhausted CD8 T cells by day 21 post infection.
Overall, our work suggests a complex role of cholinergic signaling that can both boost and limit CD8 dysfunction during chronic viral infection but has less impact on functional CD8 T cell differentiation during acute viral infection.
Classification (DDC)
500 Naturwissenschaften 570 Biowissenschaften, Biologie 610 Medizin, GesundheitLindemann, Anna Fidelia: Deciphering cholinergic signaling in CD8+ T cells during acute and chronic viral infection. - Bonn, 2026. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-89091
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-89091
@phdthesis{handle:20.500.11811/14066,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-89091,
author = {{Anna Fidelia Lindemann}},
title = {Deciphering cholinergic signaling in CD8+ T cells during acute and chronic viral infection},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2026,
month = apr,
note = {Acetylcholine is a neurotransmitter of the central and parasympathetic nervous system but can also be produced by immune cells, such as B cell and CD4 T cells. CD8 T cells play an important role in the defense against viral infections and tumor. Here, we deciphered a potential role of cholinergic signaling in effector and memory CD8 T cells during acute viral infection as well as precursor exhausted and exhausted CD8 T cells during chronic viral infection.
In our work, we showed that CD8 T cells express choline acetyltransferase (ChAT), the enzyme that catalyzes the production on acetylcholine, in a T cell receptor-dependent manner. Only antigen-experienced but not naive CD8 T cells can produce acetylcholine. During acute viral infection, ChAT expression peeks during effector phase and decreases dramatically once the virus is cleared. It is partially maintained in memory CD8 T cells. Intriguingly, even though during chronic viral infection, CD8 T cells encounter higher viral load and prolonged antigen-exposure, ChAT expression decreases with progressing T cell exhaustion, indicating an involvement of additional regulatory mechanisms.
Using specific KO mice, we demonstrated that T cell-derived ACh is redundant for effector CD8 T cell differentiation but drives T cell exhaustion. Notably, CD62L+ precursor exhausted CD8 T cells as well as conventional dendritic cells type I were increased in the lymph nodes in T cell-specific ChAT KO mice. In line with that, we showed that long term, the ratio of precursor exhausted to exhausted CD8 T cells was increased, indicating reduced T cell exhaustion.
Lastly, we showed that CD8 T cells express the α7 nicotinic receptor. Deletion of a7 nicotinic receptor in virus-specific CD8 T cells impaired the differentiation of short-lived effector cells during acute infection. Strikingly, α nicotinic receptor is crucial for the maintenance of exhausted CD8 T cells as deletion of α nicotinic receptor in CD8 T cells resulted in a loss of exhausted CD8 T cells by day 21 post infection.
Overall, our work suggests a complex role of cholinergic signaling that can both boost and limit CD8 dysfunction during chronic viral infection but has less impact on functional CD8 T cell differentiation during acute viral infection.},
url = {https://hdl.handle.net/20.500.11811/14066}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-89091,
author = {{Anna Fidelia Lindemann}},
title = {Deciphering cholinergic signaling in CD8+ T cells during acute and chronic viral infection},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2026,
month = apr,
note = {Acetylcholine is a neurotransmitter of the central and parasympathetic nervous system but can also be produced by immune cells, such as B cell and CD4 T cells. CD8 T cells play an important role in the defense against viral infections and tumor. Here, we deciphered a potential role of cholinergic signaling in effector and memory CD8 T cells during acute viral infection as well as precursor exhausted and exhausted CD8 T cells during chronic viral infection.
In our work, we showed that CD8 T cells express choline acetyltransferase (ChAT), the enzyme that catalyzes the production on acetylcholine, in a T cell receptor-dependent manner. Only antigen-experienced but not naive CD8 T cells can produce acetylcholine. During acute viral infection, ChAT expression peeks during effector phase and decreases dramatically once the virus is cleared. It is partially maintained in memory CD8 T cells. Intriguingly, even though during chronic viral infection, CD8 T cells encounter higher viral load and prolonged antigen-exposure, ChAT expression decreases with progressing T cell exhaustion, indicating an involvement of additional regulatory mechanisms.
Using specific KO mice, we demonstrated that T cell-derived ACh is redundant for effector CD8 T cell differentiation but drives T cell exhaustion. Notably, CD62L+ precursor exhausted CD8 T cells as well as conventional dendritic cells type I were increased in the lymph nodes in T cell-specific ChAT KO mice. In line with that, we showed that long term, the ratio of precursor exhausted to exhausted CD8 T cells was increased, indicating reduced T cell exhaustion.
Lastly, we showed that CD8 T cells express the α7 nicotinic receptor. Deletion of a7 nicotinic receptor in virus-specific CD8 T cells impaired the differentiation of short-lived effector cells during acute infection. Strikingly, α nicotinic receptor is crucial for the maintenance of exhausted CD8 T cells as deletion of α nicotinic receptor in CD8 T cells resulted in a loss of exhausted CD8 T cells by day 21 post infection.
Overall, our work suggests a complex role of cholinergic signaling that can both boost and limit CD8 dysfunction during chronic viral infection but has less impact on functional CD8 T cell differentiation during acute viral infection.},
url = {https://hdl.handle.net/20.500.11811/14066}
}
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