Integration of B cell responses through Toll-like receptors and antigen receptors

Abstract

Unlike other immune cells, B cells express both an antigen-specific B cell receptor (BCR) and Toll-like receptors (TLRs). Dual BCR and TLR engagement can fine-tune functional B cell responses, directly linking cell-intrinsic innate and adaptive immune programmes. Although most data regarding B cell-specific functions of the TLR signalling pathway have been obtained in mice, the discovery of patients with a deficiency in this pathway has recently provided an insight into human B cell responses. Here, we highlight the importance of the integration of signalling pathways downstream of BCRs and TLRs in modulating B cell function, focusing when possible on B cell-intrinsic roles.

Figure 1. Role of BCR and MyD88 signaling in B cells during T-independent responses

(A) Innate-like B cells, that is B-1 and marginal zone B cells, are most crucial for T-independent immune responses. Upon TLR ligation these cells downregulate integrin receptor expression, resulting in redistribution of the cells from the peritoneal cavity to the blood, lymph node and spleen. (B) Subsequently, B-1 and marginal zone B cells start to proliferate and secrete immunoglobulins and cytokines. Up-regulation of B cell-activating factor (BAFF) receptor expression leads to prolonged survival of these cells. Increased expression of co-stimulatory molecules also enables activated innate-like B cells to act as antigen-presenting cells, thereby linking T-independent and T-dependent immune responses. Most of these functional responses have been demonstrated to occur in response to direct TLR engagement in vitro; however, in vivo, these events probably require synergistic B cell receptor (BCR) and TLR engagement. (C) Recent data demonstrate the direct involvement of MyD88 in transmembrane activator and CAML interactor (TACI)-dependent nuclear factor-κB (NF-κB) signals. This can result in activation-induced cytidine deaminase (AID; an enzyme that is required for somatic hypermutation and class-switch recombination (CSR) in the germinal centre) expression and extrafollicular CSR, independently of T cell help. This pathway might also be directly activated by TLR signals, as in vitro stimulation of B cells with TLR ligands induces AID expression. Moreover, because TLR stimulation leads to upregulation of BAFF receptors, signaling via this pathway and induction of extrafollicular CSR might be enhanced by dual TACI and TLR engagement.

Figure 2. Role of BCR and MyD88 signaling in B cells during a TD immune response

Follicular B cells are activated following interaction with cognate CD4⁺ T cells and B cell receptor (BCR) engagement. Signaling through myeloid differentiation primary-response protein 88 (MyD88) during the primary response may enhance antigen presentation by B cells to T cells, as well as the secretion of cytokines such as interleukin-6 (IL-6) and interferon-γ (IFNγ) that drive T cell differentiation. Recent data suggests that TLR ligands present in viruses or viral-like particles (VLP) can directly stimulate B cells. After entering a germinal center, B cells upregulate MyD88 expression and become more responsive to TLR ligands. Signaling through MyD88 at this stage can drive increased germinal center B cells proliferation and promote class-switch recombination, especially to IgG2a and IgG2c subclasses. Soluble TLR ligands may increase B cell migration and entrance into ongoing germinal center reactions. Finally, MyD88-dependent signals can drive the differentiation of B cells into antibody-secreting plasma cells, helping to generate primary and sustain memory humoral immune responses.

Figure 3. Role of B cell intrinsic Myd88 signaling in B cell tolerance and autoimmunity

B cell development frequently results in the generation of autoreactive B cells that are removed at distinct checkpoints in the bone marrow (central tolerance) and periphery (peripheral tolerance), via a combination of mechanisms including B cell clonal deletion, receptor editing and functional anergy. Although the mechanisms remain to be determined, MyD88 signaling may impact on tolerance mechanisms, as greater autoreactivity is noted in both new emigrant and mature naïve B cell populations in patients with inborn errors in MYD88, IRAK4 and UNC93B. Autoreactive B cells also enter the mature compartment in healthy individuals, despite intact tolerance mechanisms. Murine models have demonstrated the critical importance of dual BCR- and TLR-mediated activation of autoreactive B cells. Following engagement of antigen receptors on DNA- or RNA-reactive B cells, BCR internalization shuttles DNA- or RNA-associated antigens to TLR7- and TLR9-containing intracellular compartments resulting in MyD88-dependant activation. The potential requirement for additional TLRs in activating autoreactive B cells with different specificities has not yet been addressed. Activated autoreactive B cells either undergo T-independent class-switch recombination and autoantibody production that is enhanced by BAFF; or, recruit autoreactive T cells to germinal centers resulting in T-dependent class-switch recombination, affinity maturation and pathogenic autoantibody production.

Figure 4. Role of MyD88 signaling in B cells with a regulatory function

B cells with a regulatory function can be identified in both humans and mice based on various phenotypiccharacteristics as indicated. Toll-like receptor (TLR) signals are not required for their development, but stimulation via MyD88 leads to maturation and expansion of interleukin-10 (IL-10)-expressing B cells in vitro. In mice, the suppressor function of B cells is evident in several autoimmune and infectious models. Human B cells with a regulatory function can suppress tumour necrosis factor (TNF) production by monocytes and functional deficits in human regulatory B cell function were found in patients with systemic lupus erythematosus. In contrast, increased numbers of IL-10 producing B cells have also been observed in some patients with autoimmune diseases.