Allospecific Memory B Cell Responses are Dependent on Autophagy.
Am J Transplant. 2017 Jun 16;:
Authors: Fribourg M, Ni J, Papavasiliou FN, Yue Z, Heeger PS, Leventhal JS
Long-lived, donor-reactive memory B cells (Bmem) can produce alloantibodies that mediate transplant injury. Autophagy, an intrinsic mechanism of cell organelle/component recycling, is required for Bmem survival in infectious and model antigen systems but whether autophagy impacts alloreactive Bmem is unknown. We studied mice with an inducible yellow fluorescent protein (YFP) reporter expressed under the Activation-Induced Cytidine Deaminase (AID) promoter active in B cells undergoing germinal center reactions. Up to 12 months after allogeneic sensitization, splenic YFP(+) B cells were predominantly IgD(-) IgM(-) IgG(+) and expressed CD73, CD80, and PD-L2, consistent with Bmem. Labeled cells contained significantly more cells with autophagosomes, and autophagosomes per cell than unlabeled, naïve B cells. To test for a functional link, we quantified alloantibody formation in mice with B cells conditionally deficient in the requisite autophagy gene ATG7. These experiments revealed absent B cell ATG7: a) prevented B cell autophagy, b) inhibited secondary alloantibody responses without altering primary alloantibody formation and c) diminished frequencies of alloreactive Bmem. Pharmacological autophagy inhibition with 3-methyladenine had similar effects on wild type mice. Together with new documentation of increased autophagosomes within human Bmem, our data indicate that targeting autophagy has potential for eliminating donor-reactive Bmem in transplant recipients. This article is protected by copyright. All rights reserved.
PMID: 28621910 [PubMed - as supplied by publisher]
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