[Frontiers in Bioscience 17, 2594-2615, June 1, 2012]

B cell TLRs and induction of immunoglobulin class-switch DNA recombination

Egest J. Pone1, Zhenming Xu1, Clayton A. White1, Hong Zan1, Paolo Casali1

1Institute for Immunology, School of Medicine, University of California, Irvine, CA 92697-4120, U.S.A.

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. B cell TLRs mediate TI and TD antibody responses
3.1. B cell TLRs in TI antibody responses
3.2. B cell TLRs in TD antibody responses
4. CSR mechanisms
5. TLRs and BCR synergize to induce T cell-independent CSR
5.1. TLRs and BCR synergize to induce CSR 5.2. TLRs and BCR synergize to induce AID expression and germline IH-S-CH transcription
6. Integration of TLR and BCR signaling in CSR
6.1. TLR signaling
6.2. BCR signaling
6.3. Integration of TLR and BCR signaling
7. TLRs and autoantibodies 8. Conclusions and perspectives 9. Acknowledgments
10. References

1. ABSTRACT

Toll-like receptors (TLRs) are a family of conserved pattern recognition receptors (PRRs). Engagement of B cell TLRs by microbe-associated molecular patterns (MAMPs) induces T-independent (TI) antibody responses and plays an important role in the early stages of T-dependent (TD) antibody responses before specific T cell help becomes available. The role of B cell TLRs in the antibody response is magnified by the synergy of B cell receptor (BCR) crosslinking and TLR engagement in inducing immunoglobulin (Ig) class switch DNA recombination (CSR), which crucially diversifies the antibody biological effector functions. Dual BCR/TLR engagement induces CSR to all Ig isotypes, as directed by cytokines, while TLR engagement alone induces marginal CSR. Integration of BCR and TLR signaling results in activation of the canonical and non-canonical NF-κB pathways, induction of activation-induced cytidine deaminase (AID) and germline transcription of IgH switch (S) regions. A critical role of B cell TLRs in CSR and the antibody response is emphasized by the emergence of several TLR ligands as integral components of vaccines that greatly boost humoral immunity in a B cell-intrinsic fashion.