Elsevier

Cellular Immunology

Volume 238, Issue 2, December 2005, Pages 67-75
Cellular Immunology

Review
B cells as antigen presenting cells

https://doi.org/10.1016/j.cellimm.2006.02.005Get rights and content

Abstract

Several characteristics confer on B cells the ability to present antigen efficiently: (1) they can find T cells in secondary lymphoid organs shortly after antigen entrance, (2) BCR-mediated endocytosis allows them to concentrate small amounts of specific antigen, and (3) BCR signaling and HLA-DO expression direct their antigen processing machinery to favor presentation of antigens internalized through the BCR. When presenting antigen in a resting state, B cells can induce T cell tolerance. On the other hand, activation by antigen and T cell help converts them into APC capable of promoting immune responses. Presentation of self antigens by B cells is important in the development of autoimmune diseases, while presentation of tumor antigens is being used in vaccine strategies to generate immunity. Thus, detailed understanding of the antigen presenting function of B cells can lead to their use for the generation or inhibition of immune responses.

Introduction

The significance of the antigen presenting function of B cells has been overlooked. As professional antigen presenting cells (APC), they can activate or tolerize T cells and thus participate in the generation or regulation of immune responses. However, several factors have contributed to diminish the importance of this B cell function. These include the low frequency of naïve B cells that bear a receptor for a particular antigen, their absence from skin and mucosal sites through which most pathogens and environmental antigens enter the body, and their dependence on help from activated CD4 T cells. Nevertheless, numerous studies have established that, in many circumstances, B cells can overcome these obstacles and contribute significantly as APC in the induction of T cell activation or tolerance. Here, I will provide an overview of these studies, trying to integrate all of the aspects that confer on B cells the capacity to act as APC. First, I will summarize various features regarding B cell location, endocytic capacity, and antigen processing that make them different from other APC. The activation process needed for B cells to become competent APC will be described next. Then, the role of activated B cells in the induction and amplification of immune responses will be addressed. Finally, focus will shift to presentation of antigen by resting B cells. This journey will hopefully generate a clear picture of the APC that lives within a B cell and its possible involvement as an agent or target in immune-based therapies.

Section snippets

The location of naïve B cells: when and where can they meet T cells specific for the same antigen?

Naïve B cells circulate through the blood and lymph and home to secondary lymphoid organs. There, they encounter their specific antigen and T cell clones specific for the same antigen in the early phases of the immune response. In these organs, naïve B cells and T cells are distributed in distinct zones: the lymphoid follicles for B cells, the paracortex in lymph nodes and the periarteriolar lymphoid sheaths in the spleen for T cells [1]. Various models have shown that when antigens reach these

The BCR can concentrate small amounts of antigen and determine the epitopes to be presented

After encountering antigen, APC can internalize it by three means: phagocytosis, fluid-phase pinocytosis, and receptor-mediated endocytosis. In B cells, the last process is carried out by the B cell receptor (BCR), a membrane-bound immunoglobulin that has high affinity for a given antigen. This feature allows B cells to concentrate very small quantities of their specific antigen and present it efficiently. In an elegant study, Batista and Neuberger determined that BCR affinity is directly

Antigen processing favors presentation of antigens internalized through the BCR

Antigen processing in B cells has two features that are not present in other types of APC: (1) BCR signaling ignited by antigen induces changes in the antigen processing machinery and directs its components, and (2) expression of HLA-DO modulates peptide loading of MHCII molecules by HLA-DM. These characteristics favor presentation of antigens internalized through the BCR, as will be discussed next.

In addition to recognizing antigen with high affinity with its extracellular portion, the BCR

Activation of the antigen presenting function of B cells

The characteristics reviewed thus far portray B cells as highly competent APC: they can encounter antigen and T cells in secondary lymphoid organs, internalize antigens specific for their BCR very efficiently, and give preference to their processing and presentation. According to this, the mere presence of antigen could put the antigen presenting function of B cells in motion and lead to an immune response. However, this does not happen because the frequency of B cell clones bearing a receptor

Importance of B cells in CD4 T cell priming and the initiation of immune responses

Although B cells have been shown to be able to prime naïve CD4 T cells both in vitro [45], [46] and in vivo [47], [48], [49], it has not been easy to determine the significance of their contribution in this process or if they are needed at all. Early studies in mice rendered B cell deficient by administration of anti-IgM antibodies indicated that T cell priming is deficient in the absence of B cells [50], [51], [52], [53]. However, when B cell-deficient mice were generated by gene disruption,

B cells as APC in autoimmune diseases

Autoimmune diseases represent a situation in which the antigen presenting function of B cells can have a central role. Autoreactive B and T cells exist in the normal repertoire, but their activation ensues only when many complex genetic and environmental factors concur. Autoreactive B cells are poised to be important APC both in the initiation and development of CD4 T cell driven immune responses to self antigens because their BCR cannot determine the origin of the antigen (self or foreign).

B cells as APC in vaccines

One of the most important applications of APC is vaccines, since efficient activation of CD4 T cells specific for antigens relevant in infectious and neoplasic diseases is highly desirable. Clinical trials using DC as APC in therapeutic vaccination for a variety of tumors have yielded low levels of immunity. For this reason, several investigators have turned to B cells as another source of autologous APC and have found that they have many advantages in relation to DC: a large amount of cells

T cell tolerance induction by resting B cells

Several experimental models in animals have shown that antigen presentation by resting B cells can induce T cell tolerance in vivo. Antigens used include rabbit anti-mouse Ig [87], human μ-chain [88], an encephalitogenic peptide of myelin basic protein coupled to anti-rat Ig [89], alloantigens [41], HEL [90], [91], ovalbumin [92], small nuclear ribonucleoprotein particles (snRNP) [67], and the male HY antigen [93]. In these models, B cell activation was avoided by using monovalent antigen

Concluding remarks

Numerous studies have addressed different aspects of B cell antigen presenting function in the last two decades. By integrating these data, this review will hopefully help to establish B cells as important APC in both primary and secondary immune responses. Their capacity to induce tolerance or generate immune responses depending on their activation state will make their antigen presenting function an interesting therapeutic target, as hampering of unwanted responses and generation of

Acknowledgments

I thank the National Autonomous University of Mexico for support and Dr. Paola Mina-Osorio for critical reading of the manuscript.

References (96)

  • P. Garside et al.

    Visualization of specific B and T lymphocyte interactions in the lymph node

    Science

    (1998)
  • M. Bajenoff et al.

    The strategy of T cell antigen-presenting cell encounter in antigen-draining lymph nodes revealed by imaging of initial T cell activation

    J. Exp. Med.

    (2003)
  • T. Okada et al.

    Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells

    PLoS Biol.

    (2005)
  • P. Guermonprez et al.

    The rate of dissociation between antibody and antigen determines the efficiency of antibody-mediated antigen presentation to T cells

    J. Immunol.

    (1998)
  • H.W. Davidson et al.

    Epitope-directed processing of specific antigen by B lymphocytes

    J. Cell Biol.

    (1989)
  • C. Watts et al.

    Suppressive effect of antibody on processing of T cell epitopes

    J. Exp. Med.

    (1993)
  • B. Liang et al.

    Molecular mimicry and the role of B lymphocytes in the processing of autoantigens

    Cell. Mol. Life Sci.

    (2000)
  • H. Ma et al.

    Visualization of Syk-antigen receptor interactions using green fluorescent protein: differential roles for Syk and Lyn in the regulation of receptor capping and internalization

    J. Immunol.

    (2001)
  • M.A. Putnam et al.

    Lipid raft-independent B cell receptor-mediated antigen internalization and intracellular trafficking

    J. Immunol.

    (2003)
  • H. Niiro et al.

    The B lymphocyte adaptor molecule of 32 kilodaltons (Bam32) regulates B cell antigen receptor internalization

    J. Immunol.

    (2004)
  • V.R. Aluvihare et al.

    Acceleration of intracellular targeting of antigen by the B-cell antigen receptor: importance depends on the nature of the antigen-antibody interaction

    EMBO J.

    (1997)
  • D. Lankar et al.

    Syk tyrosine kinase and B cell antigen receptor (BCR) immunoglobulin-alpha subunit determine BCR-mediated major histocompatibility complex class II-restricted antigen presentation

    J. Immunol.

    (1999)
  • K. Siemasko et al.

    Igα and Igβ are required for efficient trafficking to late endosomes and to enhance antigen presentation

    J. Immunol.

    (1999)
  • C. Li et al.

    Cooperative interaction of Ig-alpha and Ig-beta of the BCR regulates kinetics and specificity of antigen targeting

    Int. Immunol.

    (2002)
  • K. Siemasko et al.

    Receptor-facilitated antigen presentation requires the recruitment of B cell linker protein to Igα

    J. Immunol.

    (2002)
  • P.C. Cheng et al.

    MHC class II antigen processing in B cells: accelerated intracellular targeting of antigens

    J. Immunol.

    (1999)
  • V.S. Zimmerman et al.

    Engagement of B cell receptor regulates the invariant chain-dependent MHC class II presentation pathway

    J. Immunol.

    (1999)
  • D. Lankar et al.

    Dynamics of major histocompatibility complex class II compartments during B cell receptor-mediated cell activation

    J. Exp. Med.

    (2002)
  • K. Siemasko et al.

    Cutting edge: signals from the B lymphocyte antigen receptor regulate MHC class II containing late endosomes

    J. Immunol.

    (1998)
  • L. Karlsson et al.

    A novel class II MHC molecule with unusual tissue distribution

    Nature

    (1991)
  • L.K. Denzin et al.

    Negative regulation by HLA-DO of MHC class II-restricted antigen processing

    Science

    (1997)
  • M. van Ham et al.

    Modulation of the major histocompatibility complex class II-associated peptide repertoire by human histocompatibility leukocyte antigen (HLA)-DO

    J. Exp. Med.

    (2000)
  • C. Alfonso et al.

    The role of H2-O and HLA-DO in major histocompatibility complex class II-restricted antigen processing and presentation

    Immunol. Rev.

    (1999)
  • X. Chen et al.

    The expression of HLA-DO (H2-O) in B lymphocytes

    Immunol. Res.

    (2004)
  • D.J. Lenschow et al.

    Differential up-regulation of the B7-1 and B7-2 costimulatory molecules after Ig receptor engagement by antigen

    J. Immunol.

    (1994)
  • T.O. Nashar et al.

    The pathway of antigen uptake and processing dictates MHC class II-mediated B cell survival and activation

    J. Immunol.

    (2005)
  • A.E. Faassen et al.

    CD40-CD40 ligand interactions stimulate B cell antigen processing

    Eur. J. Immunol.

    (1995)
  • E.A. Ranheim et al.

    Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal

    J. Exp. Med.

    (1993)
  • M. Roy et al.

    Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses

    Eur. J. Immunol.

    (1995)
  • M.F. Mackey et al.

    The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

    J. Leukoc. Biol.

    (1998)
  • D.E. Evans et al.

    Resting B lymphocytes as APC for naive T lymphocytes: dependence on CD40 ligand/CD40

    J. Immunol.

    (2000)
  • M.K. Kennedy et al.

    Induction of B cell costimulatory function by recombinant murine CD40 ligand

    Eur. J. Immunol.

    (1994)
  • A. Clatza et al.

    CD40-induced aggregation of MHC class II and CD80 on the cell surface leads to an early enhancement in antigen presentation

    J. Immunol.

    (2003)
  • J.E. Buhlmann et al.

    In the absence of a CD40 signal, B cells are tolerogenic

    Immunity

    (1995)
  • G.A. Hollander et al.

    Induction of alloantigen-specific tolerance by B cells from CD40-deficient mice

    Proc. Natl. Acad. Sci. USA

    (1996)
  • M.E. Ozaki et al.

    CD4 T cell responses to CD40-deficient APCs: defects in proliferation and negative selection apply only with B cells as APCs

    J. Immunol.

    (1999)
  • B.O. Lee et al.

    CD40, but not CD154, expression on B cells is necessary for optimal primary B cell responses

    J. Immunol.

    (2003)
  • S. Constant et al.

    B lymphocytes can be competent antigen-presenting cells for priming CD4+ T cells to protein antigens in vivo

    J. Immunol.

    (1995)
  • Cited by (0)

    View full text