Toll-Like Receptor Agonists Synergize with CD40L to Induce Either Proliferation or Plasma Cell Differentiation of Mouse B Cells

Abstract

In a classical dogma, pathogens are sensed (via recognition of Pathogen Associated Molecular Patterns (PAMPs)) by innate immune cells that in turn activate adaptive immune cells. However, recent data showed that TLRs (Toll Like Receptors), the most characterized class of Pattern Recognition Receptors, are also expressed by adaptive immune B cells. B cells play an important role in protective immunity essentially by differentiating into antibody-secreting cells (ASC). This differentiation requires at least two signals: the recognition of an antigen by the B cell specific receptor (BCR) and a T cell co-stimulatory signal provided mainly by CD154/CD40L acting on CD40. In order to better understand interactions of innate and adaptive B cell stimulatory signals, we evaluated the outcome of combinations of TLRs, BCR and/or CD40 stimulation. For this purpose, mouse spleen B cells were activated with synthetic TLR agonists, recombinant mouse CD40L and agonist anti-BCR antibodies. As expected, TLR agonists induced mouse B cell proliferation and activation or differentiation into ASC. Interestingly, addition of CD40 signal to TLR agonists stimulated either B cell proliferation and activation (TLR3, TLR4, and TLR9) or differentiation into ASC (TLR1/2, TLR2/6, TLR4 and TLR7). Addition of a BCR signal to CD40L and either TLR3 or TLR9 agonists did not induce differentiation into ASC, which could be interpreted as an entrance into the memory pathway. In conclusion, our results suggest that PAMPs synergize with signals from adaptive immunity to regulate B lymphocyte fate during humoral immune response.

TLR3- and MyD88-Dependent Signaling Differentially Influences the Development of West Nile Virus-Specific B Cell Responses in Mice following Immunization with RepliVAX WN, a Single-Cycle Flavivirus Vaccine Candidate

“…Injection of various TLR agonists has been shown to impact B cell activation and/or proliferation. For example, injection of TLR3 agonists, in synergy with BCR signaling and CD40L, aids in B cell activation and proliferation, whereas TLR7 agonists promote development of antibody-secreting cells (43). Previous studies using virus infection models have shown that early B cell activation in draining lymph nodes as manifested by surface expression of CD69 and CD86 occurs within the first few days after infection, is polyclonal, and is transient (26,44).…”

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…Importantly, TLR activation and T cell help might interact to induce somatic mutation. TLR activation of B cells can enhance antigen presentation and increase surface expression of co-stimulatory molecules, which will facilitate non-antigen-specific interaction with T cells (76,77). Therefore, TLR activation can enhance somatic mutations in T cell-dependent or -independent B cell responses.…”

TLR7 Recognition Is Dispensable for Influenza Virus A Infection but Important for the Induction of Hemagglutinin-Specific Antibodies in Response to the 2009 Pandemic Split Vaccine in Mice

“…The subsequent cascade signal induces type I interferons (IFN-␣/␤) and production of inflammatory cytokines (31). Of these PRRs, TLR7 is important not only for the activation of the innate antiviral response but also for the induction of adaptive immunity (7,22,25,27,34,35). Heer and colleagues showed that TLR7 signaling is critical for antibody isotype class switching (22).…”

“…Recently, we have shown that TLR7 signaling is involved in the recruitment of myeloid-derived suppressor cells (MDSCs) and for the shaping of humoral immu-nity in response to IAV infection (27). Boeglin and colleagues later showed that a combination of B-cell receptor, CD40, and TLR7 stimulation on B cells augments antibody-secreting cell (ASC) differentiation (7). Collectively, these data suggest that TLR7 signaling is important in adaptive immunity, particularly in the enhancement of B-cell responses.…”