Choline acetyltransferase–expressing T cells are required to control chronic viral infection

Cox, Maureen A.; Duncan, Gordon S.; Lin, Gloria; Steinberg, Benjamin E.; Yu, Lisa; Brenner, Dirk; Buckler, Luke N.; Elia, Andrew; Wakeham, Andrew; Nieman, Brian J.; Dominguez-Brauer, Carmen; Elford, Alisha R.; Gill, Kyle T.; Kubli, Shawn P.; Haight, Jillian; Berger, Thorsten; Ohashi, Pamela S.; Tracey, Kevin J.; Olofsson, Peder S.; Mak, Tak W.

doi:10.1126/science.aau9072

Cited by 114 publications

(102 citation statements)

References 24 publications

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“…1) 38 . Another possible source of ACh are subpopulations of T cells that have been shown to code for ChAT 58 . ACh released from tuft cells, alone or together with ACh from local nerve endings and local T cells, can be expected to influence in a paracrine manner diverse epithelial cells, i.e.…”

Section: Discussionmentioning

confidence: 99%

Distribution pattern and molecular signature of cholinergic tuft cells in human gastro-intestinal and pancreatic-biliary tract

Schütz

Ruppert

Strobel

et al. 2019

Sci Rep

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Despite considerable recent insight into the molecular phenotypes and type 2 innate immune functions of tuft cells in rodents, there is sparse knowledge about the region-specific presence and molecular phenotypes of tuft cells in the human digestive tract. Here, we traced cholinergic tuft cells throughout the human alimentary tract with immunohistochemistry and deciphered their region-specific distribution and biomolecule coexistence patterns. While absent from the human stomach, cholinergic tuft cells localized to villi and crypts in the small and large intestines. In the biliary tract, they were present in the epithelium of extra-hepatic peribiliary glands, but not observed in the epithelia of the gall bladder and the common duct of the biliary tract. In the pancreas, solitary cholinergic tuft cells were frequently observed in the epithelia of small and medium-size intra- and inter-lobular ducts, while they were absent from acinar cells and from the main pancreatic duct. Double immunofluorescence revealed co-expression of choline acetyltransferase with structural (cytokeratin 18, villin, advillin) tuft cell markers and eicosanoid signaling (cyclooxygenase 1, hematopoietic prostaglandin D synthase, 5-lipoxygenase activating protein) biomolecules. Our results indicate that region-specific cholinergic signaling of tuft cells plays a role in mucosal immunity in health and disease, especially in infection and cancer.

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Section: Discussionmentioning

confidence: 99%

Distribution pattern and molecular signature of cholinergic tuft cells in human gastro-intestinal and pancreatic-biliary tract

Schütz

Ruppert

Strobel

et al. 2019

Sci Rep

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“…Mice with selective Chat deficiency within the T cell compartment have impaired vasodilation in response to infection, decreased migration of antiviral T cells into infected tissues, and substantially compromised control of chronic LCMV clone 13 infection. These findings represent a genetic proof of function for ChAT in T cells during viral infection and implicate ChAT-expressing T cells in antiviral immunity (Cox et al, 2019).…”

Section: The Collateral Scientific and Therapeutic Benefitmentioning

confidence: 63%

“…Another very recent study revealed the important role of lymphocyte-released acetylcholine in the regulation of chronic viral infections. Lymphocytic choriomeningitis virus (LCMV) infection is associated with significantly increased ChAT levels in both CD4 + and CD8 + T cells in an IL-21-dependent manner (Cox et al, 2019). Mice with selective Chat deficiency within the T cell compartment have impaired vasodilation in response to infection, decreased migration of antiviral T cells into infected tissues, and substantially compromised control of chronic LCMV clone 13 infection.…”

Section: The Collateral Scientific and Therapeutic Benefitmentioning

confidence: 99%

Collateral benefits of studying the vagus nerve in bioelectronic medicine

Pavlov

2019

Bioelectron Med

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Studies on the role of the vagus nerve in the regulation of immunity and inflammation have contributed to current preclinical and clinical efforts in bioelectronic medicine. In parallel, this research has generated new insights into the cellular and molecular mechanisms underlying the immunoregulatory functions of the vagus nerve within the inflammatory reflex. The vagus nerve and other cellular components of the inflammatory reflex are implicated in the regulation of bleeding, cancer, obesity, blood pressure, viral infections and other conditions. This collateral benefit broadens scientific horizons and provides new rationale for technological advances and therapeutic implications.

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“…In the BALT and peri-bronchial lung regions, multiple sources of ACh may contribute to cholinergic signaling whereas the alveolar space is relatively inaccessible to ACh secreted by bronchial epithelium or the vagal nerve. In addition, although our studies did not determine the primary inducers of ACh secretion by the cholinergic lymphocytes, previous studies have shown that cholinergic lymphocytes produce ACh in response to specific antigen, TLR agonists, neurotransmitters, and cytokines (11)(12)(13)47). As yet we do not know if local neurotransmitter secretion plays any role in lymphocyte ACh production The importance of ACh in recovery was indicated by the increased inflammation and aberrant tissue repair noted when Ach synthesis was inhibited.…”

Section: Discussionmentioning

confidence: 77%

“…Vagal nerve derived norepinephrine (NE) induces ACh release from cholinergic CD4 + T cells in the spleen, whereas cholinergic B-1 cells in the peritoneal cavity release ACh in response to TLR agonists, surface Ig ligation, and cholecystokinin (CCK) (11,12). During chronic hepatitis, both CD4 and CD8 cells secrete ACh in response to IL-21 (13).…”

Section: Introductionmentioning

confidence: 99%

Acetylcholine regulates pulmonary inflammation and facilitates the transition from active immunity to tissue repair during respiratory viral infection

Horkowitz

Schwartz

Álvarez

et al. 2020

Preprint

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ABSTRACTInflammatory control is critical to recovery from respiratory viral infection. Acetylcholine (ACh) secreted from non-neuronal sources, including lymphocytes, plays an important, albeit underappreciated, role in regulating immune-mediated inflammation. This study was designed to explore the role of ACh in acute viral infection and recovery. Using the murine model of influenza A, cholinergic status in the lungs and airway was examined over the course of infection and recovery. The results showed that airway ACh remained constant through the early stage of infection and increased during the peak of the acquired immune response. As the concentration of ACh increased, cholinergic lymphocytes appeared in the airway and lungs. Cholinergic capacity was found primarily in CD4 T cells, but also in B cells and CD8 T cells. The cholinergic CD4+ T cells bound to influenza-specific tetramers at the same frequency as their conventional (i.e., non-cholinergic) counterparts. In addition, they were retained in the lungs throughout the recovery phase and could still be detected in the resident memory regions of the lung up to two months after infection. Histologically, cholinergic lymphocytes were found in direct physical contact with activated macrophages throughout the lung. When ACh production was inhibited, mice exhibited increased tissue inflammation, altered lung architecture, and delayed recovery. Together, these findings point to a previously unrecognized role for ACh in the transition from active immunity to recovery and pulmonary repair following respiratory viral infection.

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Choline acetyltransferase–expressing T cells are required to control chronic viral infection

Cited by 114 publications

References 24 publications

Distribution pattern and molecular signature of cholinergic tuft cells in human gastro-intestinal and pancreatic-biliary tract

Distribution pattern and molecular signature of cholinergic tuft cells in human gastro-intestinal and pancreatic-biliary tract

Collateral benefits of studying the vagus nerve in bioelectronic medicine

Acetylcholine regulates pulmonary inflammation and facilitates the transition from active immunity to tissue repair during respiratory viral infection

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