Submitted October 21, 2008
Accepted December 24, 2008
BCR-mediated uptake of antigen linked to TLR9-ligand stimulates B-cell proliferation and antigen-specific plasma cell formation
Julia Eckl-Dorna and Facundo D. Batista*
Lymphocyte Interaction Laboratory, Cancer Research UK London Research Institute, London, United Kingdom
* Corresponding author; email: facundo.batista{at}cancer.org.uk.
The activation of toll-like receptor 9 (TLR9) expressed within B cells is associated with enhanced humoral immunity. However the role of TLR9 in the stimulation of B-cell responses, and more specifically in shaping the outcome of B-cell differentiation, remains unclear. Here, we observed that immunization with the TLR9 agonist CpG linked to protein antigen gave rise to enhanced production of antigen-specific class switched antibodies in vivo. Unlike dendritic cells, B cells are unable to acquire these conjugates by macropinocytosis and instead depend on uptake through a signalling-competent BCR, provided the overall BCR-antigen avidity exceeds a defined threshold. The resultant stimulation of intrinsic TLR9 leads to enhanced antigen-specific B-cell proliferation and differentiation to form extrafollicular plasma cells. Thus the direct conjugation of antigen and CpG reveals a mechanism that may operate during the initiation of primary immune responses, and may prove useful as adjuvants in the design of vaccination strategies.
