TLR Agonists Selectively Promote Terminal Plasma Cell Differentiation of B Cell Subsets Specialized in Thymus-Independent Responses

Abstract

Naive murine B cells are known to proliferate and differentiate in response to LPS or CpG, which bind to TLR4 and TLR9, respectively. However, the naive murine B cell compartment is heterogeneous and comprises four different B cell subsets: B-1a, B-1b, marginal zone (MZ), and follicular (FO) B cells. B-1a, B-1b, and MZ B cells are specialized in the response to thymus-independent Ag, and FO B cells are involved in the response to thymus-dependent Ag. This study was undertaken to compare those four naive B cell subsets for their responses to TLR agonists. Quantitative RT-PCR analysis revealed that expression of TLR transcripts differs quantitatively but not qualitatively from one subset to the other. All TLR agonists, with the exception of flagellin and poly(I:C), stimulate B cell proliferation whatever the subset considered. However, TLR ligation leads to massive differentiation of B-1 and MZ B cells into mature plasma cells (PC) but only marginally promotes PC differentiation of FO B cells. Moreover, TLR stimulation strongly up-regulates expression of Blimp-1 and XBP-1S, two transcription factors known to be instrumental in PC differentiation, in B-1 and MZ B cells but not in FO B cells. Altogether, our findings suggest that B-1 and MZ B cells are poised to PC differentiation in response to the microbial environment and that TLR agonists can be instrumental in stimulating Ab-mediated innate immune protection during microbial infections.

Antigen-specific B-1a antibodies induced byFrancisella tularensisLPS provide long-term protection againstF. tularensisLVS challenge

“…TLR signaling has been reported to either be inconsequential (22), required (23), or stimulatory for antibody responses to T-dependent antigens (24). For Tindependent responses, reports are equally confounded:, TLR signaling has been shown to induce IgM secretion (25,26), cellular proliferation (25,26), B-1 egress from the PerC (27), and B-1 differentiation into plasma cells (25). However, natural antibodies are produced in germ-free mice (15,16) where TLR signaling from exogenous sources is considered to be minimal.…”

A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

“…MZ B cells, together with B1 B cells in the peritoneum, are responsible for innate and rapid Ab production, which is thought to be a part of the early defence and regulation of inflammation [4,5,13]. These B-cell populations can differentiate into Ab-secreting cells by TLR ligand stimulation alone [14]. The spleen plays an important role in LPS response, and splenectomy reduces mortality and prevents liver injury in septic models [15].…”

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

“…B cells produce key inflammatory cytokines such as TNF-a and IL-6 in response to TLRs, and are especially responsive to TLR7 and TLR9 (5)(6)(7). TLR stimulation also promotes Ig class-switch recombination and Ab secretion (8). Both Abdependent and -independent TLR-stimulated B cell functions play crucial roles in protection against infectious pathogens (9).…”