E47 retroviral rescue of intrinsic B-cell defects in senescent mice.
In aging, immune responses are dramatically impaired, specifically the ability to produce protective antibodies. We previously showed that with age there is a B-cell intrinsic decrease in class switch recombination (CSR) because of a decrease in activation-induced cytidine deaminase (AID). One mechanism we have demonstrated for decreased AID includes increased mRNA degradation of the transcription factor E47, critical for AID transcription. Here, we show by means of a retroviral construct containing the DsRED reporter and the 3'UTR of E47 that the 3'UTR lowers mRNA expression, and particularly in B cells from old mice. This is the first demonstration that the E47 3'UTR directly regulates its degradation. The AID mRNA was not differentially regulated by degradation in aging. Therefore, we have here further established critical components for decreased AID with age. The major aim of this study was to establish conditions for the rescue of the intrinsic defect of aged B cells with retroviral addition of the coding region of E47 in splenic B cells to restore their ability to produce optimal AID and class switch to IgG. In this study, we show that young and old primary B cells overexpressing a stable E47 mRNA up-regulate E47, AID, and CSR and improve B-cell immune responses in senescent murine B cells. Our results provide a proof of principle for the rescue of intrinsic B-cell defects and the humoral immune response in senescence.
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Ana M
AM
Landin
Daniela
D
Frasca
Patrick
P
Harrison
Martina
M
Scallan
Richard L
RL
Riley
Bonnie B
BB
Blomberg
D020413:3' Untranslated Regions; D000375:Aging / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism*; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D020413:3' Untranslated Regions; D012333:RNA, Messenger; D058127:Transcription Factor 3; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
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