B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses

Egest J. Pone, Tonika Lam, Zheng Lou, Rui Wang, Yuhui Chen, Dongfang Liu, Aimee L. Edinger, Zhenming Xu, Paolo Casali

Research output: Contribution to journalArticle

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Abstract

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-creIγ1-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.

Original languageEnglish (US)
Pages (from-to)3065-3078
Number of pages14
JournalJournal of Immunology
Volume194
Issue number7
DOIs
StatePublished - Apr 1 2015

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Immunoglobulin Class Switching
Genetic Recombination
Antibody Formation
B-Lymphocytes
DNA
Intracellular Membranes
Phosphotransferases
Monomeric GTP-Binding Proteins
AICDA (activation-induced cytidine deaminase)
MAP Kinase Signaling System
Plasma Cells
Interleukin-4
Immunoglobulin E
Immunoglobulin M
Cell Differentiation
Immunoglobulin G
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Pone, Egest J. ; Lam, Tonika ; Lou, Zheng ; Wang, Rui ; Chen, Yuhui ; Liu, Dongfang ; Edinger, Aimee L. ; Xu, Zhenming ; Casali, Paolo. / B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses. In: Journal of Immunology. 2015 ; Vol. 194, No. 7. pp. 3065-3078.
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abstract = "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-creIγ1-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.",
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B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses. / Pone, Egest J.; Lam, Tonika; Lou, Zheng; Wang, Rui; Chen, Yuhui; Liu, Dongfang; Edinger, Aimee L.; Xu, Zhenming; Casali, Paolo.

In: Journal of Immunology, Vol. 194, No. 7, 01.04.2015, p. 3065-3078.

Research output: Contribution to journalArticle

TY - JOUR

T1 - B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses

AU - Pone, Egest J.

AU - Lam, Tonika

AU - Lou, Zheng

AU - Wang, Rui

AU - Chen, Yuhui

AU - Liu, Dongfang

AU - Edinger, Aimee L.

AU - Xu, Zhenming

AU - Casali, Paolo

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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-creIγ1-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.

AB - 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-creIγ1-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.

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