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Review
. 2019:141:105-164.
doi: 10.1016/bs.ai.2019.01.001. Epub 2019 Feb 11.

Signaling control of antibody isotype switching

Zhangguo Chen  1 , Jing H Wang  2
Affiliations
Review

Signaling control of antibody isotype switching

Zhangguo Chen et al. Adv Immunol. 2019.

Abstract

Class switch recombination (CSR) generates isotype-switched antibodies with distinct effector functions essential for mediating effective humoral immunity. CSR is catalyzed by activation-induced deaminase (AID) that initiates DNA lesions in the evolutionarily conserved switch (S) regions at the immunoglobulin heavy chain (Igh) locus. AID-initiated DNA lesions are subsequently converted into DNA double stranded breaks (DSBs) in the S regions of Igh locus, repaired by non-homologous end-joining to effect CSR in mammalian B lymphocytes. While molecular mechanisms of CSR are well characterized, it remains less well understood how upstream signaling pathways regulate AID expression and CSR. B lymphocytes express multiple receptors including the B cell antigen receptor (BCR) and co-receptors (e.g., CD40). These receptors may share common signaling pathways or may use distinct signaling elements to regulate CSR. Here, we discuss how signals emanating from different receptors positively or negatively regulate AID expression and CSR.

Keywords: Activation-induced deaminase; B cell antigen receptor; CD40; Class switch recombination; PI3K; PTEN; Signal transduction; Toll-like receptor.

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Conflict of interest statement

Compliance with Ethics Guidelines

Zhangguo Chen and Jing H. Wang declare no conflict of interest.

Figures

Figure 1.
Figure 1.. CSR model for IgG1 production at the mouse Igh locus.
Antigen-specific antibody responses are mediated by stimulating multiple receptors expressed on B cells with their cognate ligands. The signals emanating from these receptors can be categorized into three major types. Signal 1 is the initiating signal generated by BCR upon recognizing antigen. Signal 2 is generated by co-receptors (CD40, TLRs, etc.) upon recognizing their individual ligands. Signal 3 is generated by cytokine receptors (e.g., IL-4R) upon binding to specific cytokines. Signals originating from different receptors are transduced through signaling cascade and eventually lead to activation of different transcription factors (e.g., NF-κB, HoxC4 etc). The activated transcription factors induce the expression of AID and the Igh GLT (e.g., Cγ1 GLT) that allows AID to access Sγ1 region. The genomic configuration of the rearranged mouse Igh locus is shown. AID introduces point mutations into variable (V) region exon during SHM (not depicted). During CSR, AID initiates U:G mismatches in the donor Sμ and the downstream acceptor Sγ1 regions. AID-initiated U:G mismatches are processed and converted into DNA double strand breaks (DSBs) by UNG and mismatch repair (MMR) pathways. Broken S regions are rejoined via non-homologous end-joining (NHEJ), while intervening DNA is excised as a circle. Transcription is required for both SHM/CSR with promoters delineated for both V and S regions (arrows). Upon CSR, originally expressed Cμ exons are replaced by Cγ1 exons so that naïve IgM+ B cells switch to antigen experienced IgG1+ B cells (See details in text).
Figure 2.
Figure 2.. BCR signaling pathways.
BCR is activated by antigens. BCR’s adaptor Igα and Igβ contain ITAM. Engaging BCR by antigen recruits Src and Syk to phosphorylate Igα β ITAM. Phosphorylated ITAM recruits BCAP to activate the PI3K/AKT signaling pathway. Src also phosphorylates ITIM of CD22 and CD72, which recruits signaling suppressors SHP1 and SHIP1 to enforce a negative feedback regulation of BCR signaling. Signal transduction downstream of Syk can be classified into three major pathways: (1): BTK→BLNK→PLC-γ2→PKCβ→CBM complex→TRAF6/TRAF2→TAK1→NF-κB1; (2): Vav→Rac→Raf→JNK→c-Jun/AP-1; (3) BCAP→PI3K→AKT→Foxo1/Blimp-1/ID2 (See details in text).
Figure 3.
Figure 3.. CD40 signaling pathways.
In resting B cells, NIK is constitutively degraded. Upon engagement by CD40L, monomers of CD40 cluster to form CD40 trimers in membrane lipid rafts, which recruit downstream signaling molecules including TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6. TRAFs transduce signals leading to activation of NF-κB1 and NF-κB2 as well as MAPK pathways (See details in text).
Figure 4.
Figure 4.. TLR4 signaling pathways.
LPS binding protein (LBP) and MD2 facilitate the binding of LPS to CD14 and TLR4. TLR4 transduces signals via two pathways, namely, MyD88 dependent- and TRIF-dependent pathways, to activate NF-κB, MAPK and IRF3. (See details in text).
Figure 5.
Figure 5.. Transcriptional Regulation of AID.
The Aicda gene locus contains 4 conserved regulatory regions (Region 1–4). The exon 1 and 2 of AID and transcription factors that potentially bind to these regions are shown.
Figure 6.
Figure 6.. The signaling balance between PI3Ks and PTEN controls AID expression and CSR.
Signaling balance for CSR. PI3Ks catalyze the phosphorylation of PI(4,5)P2 and converts it into PIP3, whereas PTEN counteracts PI3Ks by converting PIP3 into PIP2. Increased PIP3 activates AKT which suppresses AID expression likely by regulating transcription factors FOXO1 and BLIMP-1. Reduced AID expression leads to a decreased level of CSR.
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