The sympathetic nervous system modulates CD4(+)Foxp3(+) regulatory T cells via noradrenaline-dependent apoptosis in a murine model of lymphoproliferative disease.
The sympathetic nervous system (SNS) plays a crucial role in the course and development of autoimmune disease in Fas-deficient lpr/lpr mice. As regulatory T cells (Tregs) are considered important modulators of autoimmune processes, we analyzed the interaction between the SNS and Tregs in this murine model of lymphoproliferative disease. We found that the percentage of Tregs among CD4(+) T cells is increased in the spleen, lymph nodes, and thymus of lpr/lpr mice as compared to age-matched C57Bl/6J (B6) mice. Furthermore, noradrenaline (NA), the main sympathetic neurotransmitter, induced apoptosis in B6- and lpr/lpr-derived Tregs. NA also reduced the frequency of Foxp3(+) cells and Foxp3 mRNA expression via β2-adrenoceptor (β2-AR)-mediated mechanisms in a concentration and time-dependent manner. Destruction of peripheral sympathetic nerves by 6-hydroxydopamine significantly increased the percentage of Tregs in B6 control mice to an extent comparable to aged-matched lpr/lpr mice. The concentration of splenic NA negatively correlated with the frequency of CD4(+)Foxp3(+) Tregs. Additionally, 60days after sympathectomy, a partial recovery of NA concentrations led to Treg percentages comparable to those of intact, vehicle-treated controls. Immunohistochemical analysis of the spleen revealed localization of single Foxp3(+) Tregs in proximity to NA-producing nerve fibers, providing an interface between Tregs and the SNS. Taken together, our data suggest a relation between the degree of splenic sympathetic innervation and the size of the Treg compartment. While there are few examples of endogenous substances capable of affecting Tregs, our results provide a possible explanation of how the magnitude of the Treg compartment in the spleen can be regulated by the SNS.
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany; Department of Immunophysiology, Institute of Physiology and Pathophysiology, Medical Faculty, Philipps University of Marburg, Germany. Electronic address: timo.wirth@uk-essen.de.
Timo
T
Wirth
Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Germany.
Astrid M
AM
Westendorf
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany.
Dominique
D
Bloemker
Department of Immunophysiology, Institute of Physiology and Pathophysiology, Medical Faculty, Philipps University of Marburg, Germany.
Johannes
J
Wildmann
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany.
Harald
H
Engler
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany.
Sina
S
Mollerus
Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Germany.
Munisch
M
Wadwa
Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University of Marburg, Germany.
Martin K-H
MK
Schäfer
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany.
Manfred
M
Schedlowski
Department of Immunophysiology, Institute of Physiology and Pathophysiology, Medical Faculty, Philipps University of Marburg, Germany.
Adriana
A
del Rey
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000378:metabolism*; D013154:Spleen / Q000294:innervation / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009638:Norepinephrine
Apoptosis; Autoimmune lymphoproliferative syndrome; Foxp3; Noradrenaline; Sympathetic nervous system; Systemic lupus erythematosus; Treg