Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Aug 19;13(16):1378.
doi: 10.3390/cells13161378.

Mononuclear Phagocytes, Cellular Immunity, and Nobel Prizes: A Historic Perspective

Siamon Gordon  1   2 , Annabell Roberti  2 , Stefan H E Kaufmann  3   4   5   6
Affiliations
Review

Mononuclear Phagocytes, Cellular Immunity, and Nobel Prizes: A Historic Perspective

Siamon Gordon et al. Cells. .

Abstract

The mononuclear phagocyte system includes monocytes, macrophages, some dendritic cells, and multinuclear giant cells. These cell populations display marked heterogeneity depending on their differentiation from embryonic and bone marrow hematopoietic progenitors, tissue location, and activation. They contribute to tissue homeostasis by interacting with local and systemic immune and non-immune cells through trophic, clearance, and cytocidal functions. During evolution, they contributed to the innate host defense before effector mechanisms of specific adaptive immunity emerged. Mouse macrophages appear at mid-gestation and are distributed throughout the embryo to facilitate organogenesis and clear cells undergoing programmed cell death. Yolk sac, AGM, and fetal liver-derived tissue-resident macrophages persist throughout postnatal and adult life, supplemented by bone marrow-derived blood monocytes, as required after injury and infection. Nobel awards to Elie Metchnikoff and Paul Ehrlich in 1908 drew attention to cellular phagocytic and humoral immunity, respectively. In 2011, prizes were awarded to Jules Hoffmann and Bruce Beutler for contributions to innate immunity and to Ralph Steinman for the discovery of dendritic cells and their role in antigen presentation to T lymphocytes. We trace milestones in the history of mononuclear phagocyte research from the perspective of Nobel awards bearing directly and indirectly on their role in cellular immunity.

Keywords: Nobel prizes; dendritic cells; history; homeostasis; immunity; macrophages; mononuclear phagocyte system; multinucleated giant cells; phagocytosis; plasma membrane receptors.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 2
Figure 2
Selected milestones of mononuclear phagocyte research and cellular immunity. Note indirect contributions of numerous Nobel awards. Asterisks indicate Nobel Prize laureates. Abbreviations: RES: reticulo-endothelial system, MPS: mononuclear phagocyte system, AdGPCRs: adhesion G-protein coupled receptors [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52].
Figure 3
Figure 3
The mononuclear phagocyte system. The differentiation and distribution of monocytes, macrophages, DCs, and multinucleated giant cells (MNGCs) in vivo and in vitro, based mainly on F4/80 antigen expression in mice [157], on human placenta [163], and induced pluripotent stem cells (iPSC) [164]. Fejer has developed primary macrophage cell lines from mouse fetal livers, which are superior to tumor-derived cell lines (MPI cells) [165]. Abbreviations: AGM = aorta-gonad-mesonephros, HSC = hematopoietic stem cell, MDSC = myeloid-derived suppressor cell, GM-CSF = granulocyte-macrophage colony stimulating factor, MPI = Max Planck Institute.
Figure 4
Figure 4
Morphology of mononuclear phagocytes. (A) Dendritic cell isolated from mouse spleen. Phase contrast microscopy reveals characteristic nuclear structure, cytoplasmic organelles, and dendritic processes [139]. (B) Mouse peritoneal macrophage-engulfing-antibody-coated sheep erythrocytes, note plasma membrane ruffling revealed by scanning electron microscopy. (C) F4/80+ Langerhans cells in the mouse epidermis [170]. (D,E) Mouse F4/80+ microglia in situ and montage. Note ramified processes of individual cells. (E) Striking regional morphologic heterogeneity in grey and white matter [171,172].
Figure 1
Figure 1
Selected historical figures who contributed to understanding the role of mononuclear phagocytes in cellular immunity. (A) Years 1870–1920, (B,C) 1920–1970, and (D) 1970–2020. See text and attachments for details. In this manuscript, we use the French spelling Elie Metchnikoff instead of the Russian version Ilya Metchnikov.
Figure 1
Figure 1
Selected historical figures who contributed to understanding the role of mononuclear phagocytes in cellular immunity. (A) Years 1870–1920, (B,C) 1920–1970, and (D) 1970–2020. See text and attachments for details. In this manuscript, we use the French spelling Elie Metchnikoff instead of the Russian version Ilya Metchnikov.
Figure 5
Figure 5
Sensing environment and mononuclear phagocyte responses. Schematic representation of plasma membrane opsonic Fc and complement receptors, Toll-like receptors (TLRs), and non-opsonic lectin-like and Scavenger receptors. Signaling pathways of opsonic receptors depend on ITAM and ITIM cytoplasmic domains for activatory and inhibitory responses. Cytoplasmic sensors include mitochondrial antiviral signaling (MAVS) proteins, RIG-like helicases, NOD-like receptors, and components of the DNA sensing CGAS pathway. Inflammasome activation depends on ASC and Caspase-1. Abbreviations: ITAM = immunoreceptor tyrosine-based activation, ITIM = immunoreceptor tyrosine-based inhibitory motif, NF-κB = nuclear factor kappa-light-chain enhancer of activated B cells, IRF = interferon regulatory factors, RIG = retinoic acid-inducible gene/protein; NOD = nucleotide binding and oligomerization domain; Adapted from A Pluddemann.
Figure 6
Figure 6
Heterophagy and autophagy: (A) Heterophagy is a defining property of mononuclear phagocytes. The schema shows key stages in the process of recognition, membrane, and vesicular fusion and fission, and their recycling during cargo internalization and product secretion. Two important outcomes of phagocytosis are acidification/digestion and the generation of oxygen and nitrogen radicals in host defense, critical determinants of intracellular infection. (B) The autophagy pathway employs analogous mechanisms to recognize, isolate, and degrade damaged intracellular constituents. The genetic and molecular aspects of autophagy have attracted considerable attention recently [215]. Adapted from [215,216,217]. Abbreviations: Atg = autophagy-related gene, LC3 = microtubule-associated proteins 1A/1B-light chain 3.
Figure 7
Figure 7
Paradigm of macrophage polarization. Macrophage gene expression is regulated differentially after priming by the Th1/2 cytokines and interferon gamma versus IL4/13, followed by a local innate phagocytic stimulus. The spectrum of activation extends from a signature cluster of genes characteristic of classical or alternative activation to deactivation by IL-10, tgf beta, glucocorticoid steroids [177], or by the uptake of apoptotic cells [46,223]. Polarization of macrophages mirrors that of T lymphocytes [224]. Adapted from [225].
Figure 8
Figure 8
Interactions of the MPS with other systems. We place the cells of the MPS at the center of the homeostatic networks which interact reciprocally with all other cellular systems of the body. Illustrative examples of such systemic tissue interactions are given in the text.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Darwin C., Beer G. On the Origin of Species. OUP Oxford; Oxford, UK: 2008.
    1. Harris H. The Birth of the Cell. Yale University Press; New Haven, CT, USA: 2000.
    1. Meyer H., Ackerknecht E.H. Rudolf Virchow: Doctor, Statesman, Anthropologist. Books Abroad. 1955;29:358. doi: 10.2307/40094696. - DOI
    1. Brock T.D., Geison G.L., Dubos R.J. Pasteur and Modern Science. Springer; Berlin/Heidelberg, Germany: 2014.
    1. Bernard C. An Introduction to the Study of Experimental Medicine. 1865. [(accessed on 11 August 2024)]. Available online: https://www.britannica.com/topic/An-Introduction-to-the-Study-of-Experim....

Grants and funding

This research received no external funding.

LinkOut - more resources