Regulatory T cells protect mice against coxsackievirus-induced myocarditis through the transforming growth factor beta-coxsackie-adenovirus receptor pathway.
BACKGROUND
Coxsackievirus B3 infection is an excellent model of human myocarditis and dilated cardiomyopathy. Cardiac injury is caused either by a direct cytopathic effect of the virus or through immune-mediated mechanisms. Regulatory T cells (Tregs) play an important role in the negative modulation of host immune responses and set the threshold of autoimmune activation. This study was designed to test the protective effects of Tregs and to determine the underlying mechanisms.


RESULTS
Carboxyfluorescein diacetate succinimidyl ester-labeled Tregs or naïve CD4(+) T cells were injected intravenously once every 2 weeks 3 times into mice. The mice were then challenged with intraperitoneal coxsackievirus B3 immediately after the last cell transfer. Transfer of Tregs showed higher survival rates than transfer of CD4(+) T cells (P=0.0136) but not compared with the PBS injection group (P=0.0589). Interestingly, Tregs also significantly decreased virus titers and inflammatory scores in the heart. Transforming growth factor-beta and phosphorylated AKT were upregulated in Tregs-transferred mice and coxsackie-adenovirus receptor expression was decreased in the heart compared with control groups. Transforming growth factor-beta decreased coxsackie-adenovirus receptor expression and inhibited coxsackievirus B3 infection in HL-1 cells and neonatal cardiac myocytes. Splenocytes collected from Treg-, CD4(+) T-cell-, and PBS-treated mice proliferated equally when stimulated with heat-inactivated virus, whereas in the Treg group, the proliferation rate was reduced significantly when stimulated with noninfected heart tissue homogenate.


CONCLUSIONS
Adoptive transfer of Tregs protected mice from coxsackievirus B3-induced myocarditis through the transforming growth factor beta-coxsackie-adenovirus receptor pathway and thus suppresses the immune response to cardiac tissue, maintaining the antiviral immune response.
Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada.
Yu
Y
Shi
Masahiro
M
Fukuoka
Guohua
G
Li
Youan
Y
Liu
Manyin
M
Chen
Michael
M
Konviser
Xin
X
Chen
Mary Anne
MA
Opavsky
Peter P
PP
Liu
D056704:Adaptive Immunity / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000502:physiology*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt