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

Key Points

  • B cells express both a clonally rearranged, antigen-specific B cell receptor (BCR) and germline-encoded, pattern-recognizing Toll-like receptors (TLRs). Dual BCR and TLR engagement is responsible for fine-tuning functional B cell responses, directly linking innate and adaptive immune functions.

  • Consistent with the stronger in vitro responses of innate-like B-1 and marginal zone B cells to TLR ligands, T-independent B cell activation and antigen-specific antibody production is promoted by B cell-intrinsic TLR signalling that is dependent on myeloid differentiation primary-response protein 88 (MYD88).

  • Although not absolutely required for T-dependent B cell responses, B cell-intrinsic MYD88 signalling can enhance T-dependent antibody responses by driving class-switch recombination, promoting the differentiation of germinal centre and memory B cells into antibody-secreting plasma cells, and supporting effector T cell differentiation through cytokine secretion. The requirement for MYD88 signalling in B cells depends on both the nature of the protein antigen and the TLR ligand(s).

  • In addition to recognizing pathogens, B cell TLRs can recognize self ligands, in particular nuclear antigens derived from apoptotic cells. Activation of autoreactive B cells by dual BCR and TLR engagement has a crucial role in autoimmune pathogenesis and probably explains the restricted autoantibody repertoire of many human autoimmune diseases.

  • B cell-intrinsic TLR activation promotes the differentiation and expansion of interleukin-10-producing regulatory B cell populations that are able to suppress autoimmunity and limit immune responses to infectious challenges.

  • Activating mutations in signalling adaptors downstream of the BCR (including CARMA1, CD79a and CD79b) or of TLRs (such as MYD88) implicate dual BCR and TLR activation as a key survival signal in refractory human B cell lymphomas.

  • Although most of the above findings are derived from mouse models, emerging data from MYD88- or IL-1R-associated kinase 4 (IRAK4)-deficient patients and from human genome-wide association studies of autoimmunity and malignancy have begun to highlight the importance of BCR and TLR integration in human B cell tolerance and immune responses.

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.

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Figure 1: The role of BCR and MYD88 signalling in B cells during T-independent responses.
Figure 2: The role of BCR and MYD88 signalling in B cells during T-dependent immune responses.
Figure 3: The role of B cell-intrinsic MYD88 signalling in B cell tolerance and autoimmunity.
Figure 4: The role of MYD88 signalling in B cells with a regulatory function.

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Acknowledgements

This work was supported by US National Institutes of Health grants HD037091, HL075453, AI084457 and AI071163 (to D.J.R.); a Cancer Research Institute Predoctoral Training Grant (to M.A.S.); Rheumatology T32 Postdoctoral Training Grant 5T32AR007108 (to S.W.J.) and German Research Foundation (Deutsche Forschungsgemeinschaft) grant ME2709/2-1 (to A.M.B.).

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Glossary

B-1 cells

IgMhiIgDlowMAC1+B220lowCD23 cells that are dominant in the peritoneal and pleural cavities. The size of the B-1 cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have low affinity and broad specificity.

Marginal zone B cells

Mature B cells that are enriched mainly in the spleen marginal zone, which is located at the border of the white pulp.

Follicular B cells

A recirculating mature B cell subset that populates the follicles of the spleen and lymph nodes.

Germinal centre

A lymphoid structure that arises in follicles after immunization with, or exposure to, a T-dependent antigen. This structure is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

Class-switch recombination

(CSR). The process by which a heavy-chain variable-region gene segment that is attached to one heavy-chain constant-region gene segment in the expressed heavy-chain gene is recombined with a downstream constant-region gene segment, leading to the expression of a new antibody class.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidney. Patients with SLE generally have abnormal B and T cell function.

Wiskott–Aldrich syndrome

A life-threatening X-linked immunodeficiency caused by mutations in the gene encoding Wiskott–Aldrich syndrome protein. It is characterized by thrombocytopenia with small platelets, eczema, recurrent infections caused by immunodeficiency and an increased incidence of autoimmune manifestations and malignancies.

Common variable immune deficiency syndrome

(CVID syndrome). The most common symptomatic primary antibody deficiency, characterized by decreased levels of serum immunoglobulins and a low or normal number of B cells. Most patients suffer from recurrent infections, predominantly of the respiratory and gastrointestinal tracts. The incidence of malignancies, such as gastric carcinoma or lymphoma, is increased in patients with CVID syndrome.

μMT mice

These mice carry a stop codon in the first membrane exon of the immunoglobulin μ-chain constant region. They lack IgM+ B cells, and B cell development is arrested before the differentiation stage at which IgD can be expressed.

Ribi adjuvant

An emulsion containing a metabolizable oil, a detergent and bacterial products, including the TLR4 ligand monophosphoryl lipid A.

Hapten

A molecule that can bind to antibodies but cannot by itself elicit an immune response. Antibodies that are specific for a hapten can be generated when the hapten is chemically linked to a protein carrier that can elicit a T cell response.

Virus-like particles

(VLPs). Virion-like structures that are formed from the self-assembly of viral envelope or capsid proteins in vitro. VLPs are not infectious because they do not contain a viral genome.

Antinuclear antibodies

(ANAs). Heterogeneous autoantibodies that are specific for one or more antigens present in the nucleus, including chromatin, nucleosomes and ribonuclear proteins. ANAs are found in association with many different autoimmune diseases.

Immune complexes

Complexes of antigen bound to antibody and, sometimes, components of the complement system. The levels of immune complexes are increased in many autoimmune disorders, in which they become deposited in tissues and cause tissue damage.

MRL–lpr mice

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus. The lpr mutation causes a defect in CD95 (also known as FAS), preventing apoptosis of activated lymphocytes. The MRL strain contributes disease-associated mutations that have yet to be identified.

MRL–gld mice

A mouse strain that has a naturally occurring mutation in CD95 ligand that causes a generalized lymphoproliferative disease, similar to that of MRL–lpr mice.

T regulatory type 1 cells

A subset of CD4+ regulatory T cells that secrete high levels of IL-10 and that downregulate TH1 and TH2 cell responses in vitro and in vivo through one or more contact-independent mechanisms that are mediated by the secretion of soluble IL-10 and TGFβ1.

Apolipoprotein E-deficient mice

(Apoe−/− mice). A widely used mouse model that is prone to develop atherosclerosis because the mice have high levels of remnant lipoproteins (a type of atherogenic lipoprotein). This lipoprotein abnormality is caused by the genetic absence of apolipoprotein E, which normally clears remnant lipoproteins from the bloodstream by interacting with hepatocytes.

Low-density lipoprotein receptor-deficient mice

(Ldlr−/− mice). A mouse model of atherosclerosis caused by a targeted deletion of the gene encoding the low-density lipoprotein receptor (LDLR). In humans, homozygous mutations in LDLR cause familial hypercholesterolaemia, a disease characterized by pronounced hyperlipidaemia and accelerated atherosclerotic cardiovascular disease. Ldlr−/− mice fed a high-fat, high-cholesterol diet have a plasma lipoprotein profile resembling humans and develop aortic lesions that are morphologically similar to human atherosclerotic plaques.

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Rawlings, D., Schwartz, M., Jackson, S. et al. Integration of B cell responses through Toll-like receptors and antigen receptors. Nat Rev Immunol 12, 282–294 (2012). https://doi.org/10.1038/nri3190

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