Editorial: Phagocytic B cells: déjà vu all over again?

In 1908, Ilya Metchnikov and Paul Erlich shared the Nobel Prize in physiology or medicine for their contributions to the field of Immunology [1, 2]. Metchnikov was recognized for his theory of immunity based on observations of phagocytes in larval echinoderms, whereas Erlich was honored for work leading to his side-chain hypothesis of humoral immune specificity. This event marked formal recognition that although neither view alone satisfactorily explained the phenomenon of immunity, both types of mechanisms were likely at work. Indeed, this dichotomy of broad mechanistic explanations—the innate sensing, ingestion, and destruction of irritating substances versus the induction of effectors with ligand specificity—was debated, even as the prize was awarded. Indeed, sorting out the relative contributions of these processes to the overall phenomenon of immunity remains relevant today. Now, a century beyond Metchnikov and Erlich’s shared prize, two papers in this issue of the Journal of Leukocyte Biology report the existence of phagocytic B cells in mice [3, 4]. Although prior reports had identified B cells with similar properties in fish, amphibians, and reptiles [5, 6], the current observations extend these earlier findings and provide compelling evidence that phagocytic B cells are also a feature of mammalian immune systems. These papers and their implications invite us to revisit the intersection of these ideas, as well as more global questions within their compass. Each of the two papers details a purposeful series of experiments that reveals phagocytic capacity among B lineage cells, although Nakashima et al. [3] focus on B cells obtained from the liver, whereas Parra et al. [4] deal largely with free peritoneal cavity B cells. The underlying conceptual threads of both reports are strikingly consistent and parallel, yielding a picture in which cells in the peritoneal cavity and liver B1 and B2 subsets display phagocytic activity, accompanied by bactericidal and antigen-presenting capacities (Fig. 1). In each paper, the opening observation is that liver or peritoneal cavity B cells can internalize latex beads and killed bacteria. Based on microscopy and specialized, single-cell cytofluorimetric analyses, each group confirms that this is genuine intracellular internalization rather than surface association. Moreover, both groups find that the numbers of particles internalized are dose-dependent and, as would be expected for phagocytic events, when the particulates exceed a certain size, phagocytosis does not occur. Following these primary observations, both groups undertake a series of unique but harmonizing studies to rule out BCR-mediated internalization and to substantiate that this process displays the molecular and intracellular trafficking characteristics of bona fide phagocytic activity. In this regard, Parra et al. [4] show that BCR-blocking antibodies fail to influence the internalization of these particulates, indicating independence from the cells’ adaptive immune receptor. Extending this idea, Nakashima et al. [3] find that fresh serum enhances the rate and extent of internalized particles and that heat inactivation destroys this enhancement, thereby implicating complement-mediated opsonization in these processes. Both groups go on to show that agents capable of disrupting cytoskeletal and microtubule integrity, such as cytochalasin B and colchicine, markedly reduce the ingestion of particulates. In a series of well-crafted experiments with fluorescently marked particles, Parra et al. [4] find that phagocytosed particles colocalize with lysosome-associated membrane protein-1, indicating that they are likely trafficked to phagolysosomal compartments. In accord with this intracellular trafficking pattern, both papers find that phagocytic action is accompanied by bactericidal capacity. In fact, Parra et al. [4] find that phagocytic peritoneal cavity B1 cells were significantly more effective than peritoneal macrophages in this capacity. Despite their general congruency, the two papers differ in terms of the subsets and proportions of B cells with phagocytic activity. Thus, Parra et al. [4] find that among peritoneal cavity cells, only those of the B1 subset are phagocytic, whereas peritoneal cavity B2 B cells exhibit no significant activity. In contrast,