Review ArticleB cells responses and cytokine production are regulated by their immune microenvironment
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.
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