Elsevier

Cytokine

Volume 74, Issue 2, August 2015, Pages 318-326
Cytokine

Review Article
B cells responses and cytokine production are regulated by their immune microenvironment

https://doi.org/10.1016/j.cyto.2015.02.007Get rights and content

Highlights

Abstract

The adaptive immune system consists of two types of lymphocytes: T and B cells. These two lymphocytes originate from a common precursor, yet are fundamentally different with B cells mediating humoral immunity while T cells mediate cell mediated immunity. In cytokine production, naïve T cells produce multiple cytokines upon activation while naïve activated B cells do not. B cells are capable of producing cytokines, but their cytokine production depends on their differentiation state and activation conditions. Hence, unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines. Many cytokines act on B cells as well. Here, we discuss several cytokines and their effects on B cells including: Interleukins, IL-7, IL-4, IL-6, IL-10, and Interferons, IFN-α, IFN-β, IFN-γ. These cytokines play important roles in the development, survival, differentiation and/or proliferation of B cells. Certain chemokines also play important roles in B cell function, namely antibody production. As an example, we discuss CCL28, a chemokine that directs the migration of plasma cells to mucosal sites. We conclude with a brief overview of B cells as cytokine producers and their likely functional consequences on the immune response.

Introduction

The immune system is a highly evolved mechanism designed to protect us from pathogens present in our environment. If a pathogen breaches our primary defense mechanisms, represented by barrier tissues such as the skin and mucosal epithelia, we are equipped with an arsenal of molecular and cellular weaponry that has adapted over millions of years of host-pathogen interactions. In its earliest stages, the immune system consisted of a group of generic receptors capable of recognizing conserved pathogen patterns that could elicit a host response [1], [2], [3]. The ability to recognize conserved pathogen associated molecular patterns or “PAMP’s” is a fundamental characteristic of the innate immune system. Despite the capacity to recognize conserved patterns present on pathogens, the innate system lacks the ability to remember a previous assailant and respond with a larger and more rapid response against that insult.

The adaptive immune system includes of two main types of lymphocytes: T and B cells. Each of these originate from different lymphoid organs: the thymus and bone marrow, respectively. The ability to generate diverse antigen receptors, a key feature associated with the adaptive immune system, is driven by the gene AID, which encodes an activation-induced deaminase. This gene plays a crucial role in the recombination process that generates a variable T or B cell receptor (TCR/BCR) [4], [5]. The two main types of lymphocytes work in concert to produce an adaptive immune response.

We begin this review with an overview of B cell development and differentiation. Given the large number of cytokines that act on B cells we have chosen to focus on several that play significant roles in the development, survival, differentiation and proliferation of B cells. Interleukins IL-7, IL-4, IL-6, and IL-10 are discussed because of their role in B cell development, B cell proliferation and isotype secretion, and the ability of B cells to regulate the immune response, respectively. The interferons: IFN-α, IFN-β, and IFN-γ, also play important roles in the development of B cell responses. Next, we discuss CCL28, a chemotactic cytokine (chemokine) that recruits IgA+ plasma cells to the mucosal tissues. For a list of the cytokines discussed and their functions see Table 1. Finally, we conclude with a brief overview of B cells as cytokine producers and their effects on the immune system.

Section snippets

B cell development, differentiation, and their role in adaptive immunity

B cells undergo a molecular process to rearrange the heavy and light chains of their immunoglobulin genes. This is known as V–D–J and V–J recombination [6] and it applies to the heavy and light chains, respectively. It occurs in the fetal liver and bone marrow and is supported by stromal cell-derived IL-7 [7]. Upon completion of this rearrangement, B cells express a unique BCR [8]. The BCR is required for further B cell development and survival [9]. Upon exiting the bone marrow a B cell is

Cytokines that act on B cells

Cytokines are proteins produced and secreted by a variety of cells including stromal cells, fibroblasts, and endothelial cells. In the immune system they are produced by leukocytes and exert their function on other leukocytes or tissues that express the cytokine receptor [28]. Some of them are called interleukins (between leukocytes). The term interleukin (IL) was first used in 1979 to describe two different molecules secreted by leukocytes with a similar molecular weight. These two early

Interferons that act on B cells

Several interferons, including IFN-α, IFN-β, and IFN-γ have interesting effects on B cells [95]. Both type I and type II IFN’s are involved in generating an antiviral state. They accomplish this by regulating both branches of the immune system. However, sustained antiviral responses are dependent on IFN-γ [96], [97], [98]. Beyond their ability to interfere with the replication of viruses they also have a role in the type of response produced. For example, both types of interferons up-regulate

Chemokines and B cells

Chemokines are small secreted chemotactic cytokines that control both the innate and adaptive branches of the immune system. In the immune system, their primary function is to direct the migration of cells of the immune system in the body; hence they are often considered the ‘traffic directors’ of the immune system because they guide different leukocyte subsets to a given destination. Here we will discuss CCL28 as an example, because of its important role in directing B cells, specifically IgA+

B cells as cytokine producers

Naïve B cells do not secrete many cytokines upon activation. In contrast, naïve T cells initiate cytokine production almost immediately after activation. This inherent difference between T and B cells reflects the fact that B cells require additional signaling beyond activation to become cytokine producers. The additional signaling can be provided by the immune microenvironment and specific differentiation stages of the B cell. For example, the main cytokines produced by naïve B cells upon

Acknowledgments

We would like to thank Dr. Amanda M. Burkhardt for her critical review of the manuscript. This work was supported by NIAID NIH Grants R01 AI93548 and R21 AI096278 (to AZ). MIV was supported by NSF-GK-12 Grant DGE-0638751 and NIH MBRS-IMSD Grant GM055246. JCD was supported by CONACYT/SEP #329416/BC-1455.

References (130)

  • A.L. Wurster et al.

    Interleukin-4-mediated protection of primary B cells from apoptosis through Stat6-dependent up-regulation of Bcl-xL

    J Biol Chem

    (2002)
  • M.H. Kaplan et al.

    Stat6 is required for mediating responses to IL-4 and for development of Th2 cells

    Immunity

    (1996)
  • S. Matsukura et al.

    Expression of IL-6, IL-8, and RANTES on human bronchial epithelial cells, NCI-H292, induced by influenza virus A

    J Allergy Clin Immunol

    (1996)
  • J.B. Eggesbo et al.

    LPS induced release of IL-1 beta, IL-6, IL-8 and TNF-alpha in EDTA or heparin anticoagulated whole blood from persons with high or low levels of serum HDL

    Cytokine

    (1996)
  • Y. Bao et al.

    The immune potential and immunopathology of cytokine-producing B cell subsets: a comprehensive review

    J Autoimmun

    (2014)
  • K. Yoshizaki et al.

    Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease

    Blood

    (1989)
  • R. Kuhn et al.

    Interleukin-10-deficient mice develop chronic enterocolitis

    Cell

    (1993)
  • T. Suda et al.

    Identification of a novel thymocyte growth-promoting factor derived from B cell lymphomas

    Cell Immunol

    (1990)
  • K. Yanaba et al.

    A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses

    Immunity

    (2008)
  • P.A. Blair et al.

    CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients

    Immunity

    (2010)
  • T. Taniguchi et al.

    The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors

    Curr Opin Immunol

    (2002)
  • C.A. Janeway et al.

    Innate immune recognition

    Annu Rev Immunol

    (2002)
  • J.A. Hoffmann

    The immune response of Drosophila

    Nature

    (2003)
  • S.G. Conticello et al.

    Evolution of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases

    Mol Biol Evol

    (2005)
  • S.L. Nutt et al.

    Commitment to the B-lymphoid lineage depends on the transcription factor Pax5

    Nature

    (1999)
  • V.A. Illera et al.

    Apoptosis in splenic B lymphocytes. Regulation by protein kinase C and IL-4

    J Immunol

    (1993)
  • J. Jacob et al.

    Intraclonal generation of antibody mutants in germinal centres

    Nature

    (1991)
  • A. Cerutti et al.

    Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes

    Nat Rev Immunol

    (2013)
  • S. Pillai et al.

    The follicular versus marginal zone B lymphocyte cell fate decision

    Nat Rev Immunol

    (2009)
  • A. Radbruch et al.

    Competence and competition: the challenge of becoming a long-lived plasma cell

    Nat Rev Immunol

    (2006)
  • K. Dorshkind et al.

    Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential

    Nat Rev Immunol

    (2007)
  • R.R. Hardy

    B-1 B cell development

    J Immunol

    (2006)
  • K. Hayakawa et al.

    The “Ly-1 B” cell subpopulation in normal immunodefective, and autoimmune mice

    J Exp Med

    (1983)
  • R.R. Hardy et al.

    B cell development pathways

    Annu Rev Immunol

    (2001)
  • A. Hever et al.

    Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator

    Proc Natl Acad Sci USA

    (2007)
  • M.D. Cooper et al.

    The functions of the thymus system and the bursa system in the chicken. 1966

    J Immunol

    (2006)
  • J.D. Bouaziz et al.

    Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice

    Proc Natl Acad Sci USA

    (2007)
  • F. Mackay et al.

    Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations

    J Exp Med

    (1999)
  • N. Baumgarth et al.

    CD4+ T cells derived from B cell-deficient mice inhibit the establishment of peripheral B cell pools

    Proc Natl Acad Sci USA

    (2000)
  • P.A. Gonnella et al.

    B cell-deficient (mu MT) mice have alterations in the cytokine microenvironment of the gut-associated lymphoid tissue (GALT) and a defect in the low dose mechanism of oral tolerance

    J Immunol

    (2001)
  • X. Yang et al.

    Gene knockout B cell-deficient mice demonstrate that B cells play an important role in the initiation of T cell responses to Chlamydia trachomatis (mouse pneumonitis) lung infection

    J Immunol

    (1998)
  • C. Brocker et al.

    Evolutionary divergence and functions of the human interleukin (IL) gene family

    Hum Genomics

    (2010)
  • C.A. Dinarello et al.

    Interleukins

    Annu Rev Med

    (1986)
  • F.L. van de Veerdonk et al.

    IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist

    Proc Natl Acad Sci USA

    (2012)
  • I. Ushach et al.

    METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages

    Clin Immunol

    (2014)
  • D. Boraschi et al.

    IL-37: a new anti-inflammatory cytokine of the IL-1 family

    Eur Cytokine Netw

    (2011)
  • A.E. Namen et al.

    B cell precursor growth-promoting activity. Purification and characterization of a growth factor active on lymphocyte precursors

    J Exp Med

    (1988)
  • R.G. Goodwin et al.

    Human interleukin 7: molecular cloning and growth factor activity on human and murine B-lineage cells

    Proc Natl Acad Sci USA

    (1989)
  • A.E. Namen et al.

    Stimulation of B-cell progenitors by cloned murine interleukin-7

    Nature

    (1988)
  • U. von Freeden-Jeffry et al.

    Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine

    J Exp Med

    (1995)
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