In:
The Journal of Immunology, The American Association of Immunologists, Vol. 194, No. 7 ( 2015-04-01), p. 3065-3078
Kurzfassung:
Class switch DNA recombination (CSR) is central to the maturation of the Ab response because it diversifies Ab effector functions. Like somatic hypermutation, CSR requires activation-induced cytidine deaminase (AID), whose expression is restricted to B cells, as induced by CD40 engagement or dual TLR-BCR engagement (primary CSR-inducing stimuli). By constructing conditional knockout Igh+/Cγ1-creRab7fl/fl mice, we identified a B cell–intrinsic role for Rab7, a small GTPase involved in intracellular membrane functions, in mediating AID induction and CSR. Igh+/Cγ1-creRab7fl/fl mice displayed normal B and T cell development and were deficient in Rab7 only in B cells undergoing IghCγ1-cre Iγ1-Sγ1-Cγ1-cre transcription, as induced—like Igh germline Iγ1-Sγ1-Cγ1 and Iε-Sε-Cε transcription—by IL-4 in conjunction with a primary CSR-inducing stimulus. These mice could not mount T-independent or T-dependent class-switched IgG1 or IgE responses while maintaining normal IgM levels. Igh+/Cγ1-creRab7fl/fl B cells showed, in vivo and in vitro, normal proliferation and survival, normal Blimp-1 expression and plasma cell differentiation, as well as intact activation of the noncanonical NF-κB, p38 kinase, and ERK1/2 kinase pathways. They, however, were defective in AID expression and CSR in vivo and in vitro, as induced by CD40 engagement or dual TLR1/2-, TLR4-, TLR7-, or TLR9-BCR engagement. In Igh+/Cγ1-creRab7fl/fl B cells, CSR was rescued by enforced AID expression. These findings, together with our demonstration that Rab7-mediated canonical NF-κB activation, as critical to AID induction, outline a novel role of Rab7 in signaling pathways that lead to AID expression and CSR, likely by promoting assembly of signaling complexes along intracellular membranes.
Materialart:
Online-Ressource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.1401896
Sprache:
Englisch
Verlag:
The American Association of Immunologists
Publikationsdatum:
2015
ZDB Id:
1475085-5
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