Evolutionary and functional relationships of B cells from fish and mammals: insights into their novel roles in phagocytosis and presentation of particulate antigen

Abstract

The evolutionary origins of Ig-producing B cells appear to be linked to the emergence of fish in this planet. There are three major classes of living fish species, which from most primitive to modern they are referred to as agnathan (e.g., lampreys), Chondrichthyes (e.g., sharks), and teleost fish (e.g., rainbow trout). Agnathans do not have immunoglobulin- producing B cells, however these fish contain a subset of lymphocytes-like cells producing type B variable lymphocyte receptors (VLRBs) that appear to act as functional analogs of immunoglobulins. Chondrichthyes fish represent the most primitive living species containing bona-fide immunoglobulin-producing B cells. Their B cells are known to secrete three types of antibodies, IgM, IgW and IgNAR. Teleost fish are also called bony fish since they represent the most ancient living species containing true bones. Teleost B cells produce three different immunoglobulin isotypes, IgM, IgD and the recently described IgT. While teleost IgM is the principal player in systemic immunity, IgT appears to be a teleost immunoglobulin class specialized in mucosal immune responses. Thus far, three major B cell lineages have been described in teleost, those expressing either IgT or IgD, and the most common lineage which co-expresses IgD and IgM. A few years ago, the study of teleost fish B cells revealed for the first time in vertebrates the existence of B cell subsets with phagocytic and intracellular bactericidal capacities. This finding represented a paradigm shift as professional phagocytosis was believed to be exclusively performed by some cells of the myeloid lineage (i.e., macrophages, monocytes, neutrophils). This phagocytic capacity was also found in amphibians and reptiles, suggesting that this innate capacity was evolutionarily conserved in certain B cell subsets of vertebrates. Recently, the existence of subsets of B cells with phagocytic and bactericidal abilities have also been confirmed in mammals. Moreover, it has been shown that phagocytic B-1 B cells have a potent ability to present particulate antigen to CD4+ T cells. Thus, studies carried out originally on fish B cells have lead to the discovery of new innate and adaptive roles of B cells in mammals. This review will concentrate on the evolutionary and functional relationships of fish and mammalian B cells, focusing mainly on the newly discovered roles of these cells in phagocytosis, intracellular killing and presentation of particulate antigen.

Fig. (1). Transmission and scanning electron microscopy analysis of fish phagocytic B cells

Rainbow trout IgM⁺ B cells can be seen in the process of internalizing 1 μm or 2 μm latex beads (left images) or with internalized beads (right images). Upper and middle panels are TEM images, whereas the bottom panels are SEM images. Beads are marked with a red X. Images were taken from (51) and reproduced with permission of Nature Immunology.

Fig. (2). Transmission electron microscopy analysis of murine phagocytic B-1b B cells

Murine B-1b B cells can be seen in the process of internalizing 1μm latex beads (top images) or with internalized beads (bottom images). Beads are marked with a red X. Images were taken from (88) and reproduced with permission of Journal of Leukocyte Biology.

Fig. (3). Schematic representation of potential roles of phagocytic B cells in mammalian immunity

Upon phagocytosis of the particle, scenario 1 (top) hypothesizes a lack or inhibition of antibody production. In this scenario, phagocytic B cells could embrace functions characteristic of professional phagocytes and APCs. Some of these functions, including microbial killing, presentation of particulate antigent to CD4 T cells and secretion of Il-12, have recently been reported (88, 91). In addition, these phagocytic B cells could also produce pro- or antiinflammatory cytokines depending on whether they have ingested microbes or apoptotic bodies respectively. Scenario 2 (bottom) hypothesizes that upon phagocytosis of the particle, phagocytic B cells are activated and produce immunoglobulins. These natural Igs could be produced in situations of acute infection with the goal of recognizing microbial PAMPs and clearing microbes. Alternatively PerC B-1 B cells could ingest commensal bacteria leaking from the gut and going into the PerC. Upon phagocytosis of the commensal, the phagocytic PerC B-1 B cells would migrate into into GALT where this cell would either produce IgM or would class-switch to produce low affinity IgA. The secreted antibody would be transported into the gut lumen where it would contribute to the process of immune exclusion. Red or green Y represents non-produced or produced immunoglobulin respectively. Green, orange and red lines represent processes that will, may or won’t happen respectively.