Abstract
Dendritic cells (DCs) are crucial gatekeepers of the balance between immunity and tolerance. They exist in two functional states, immature or mature, that refer to an information-sensing versus an information-transmitting state, respectively. Historically, the term DC maturation was used to describe the acquisition of immunostimulatory capacity by DCs following their triggering by pathogens or tissue damage signals. As such, immature DCs were proposed to mediate tolerance, whereas mature DCs were associated with the induction of protective T cell immunity. Later studies have challenged this view and unequivocally demonstrated that two distinct modes of DC maturation exist, homeostatic and immunogenic DC maturation, each with a distinct functional outcome. Therefore, the mere expression of maturation markers cannot be used to predict immunogenicity. How DCs become activated in homeostatic conditions and maintain tolerance remains an area of intense debate. Several recent studies have shed light on the signals driving the homeostatic maturation programme, especially in the conventional type 1 DC (cDC1) compartment. Here, we highlight our growing understanding of homeostatic DC maturation and the relevance of this process for immune tolerance.
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Acknowledgements
The authors thank C. Reis e Sousa (The Francis Crick Institute; UK), B. Lambrecht (VIB-UGent Center for Inflammation Research; Belgium), C. Scott (VIB-UGent Center for Inflammation Research; Belgium), H. Hammad (VIB-UGent Center for Inflammation Research; Belgium), C. Maueröder (VIB-UGent Center for Inflammation Research; Belgium), F. Osorio (Institute of Biomedical Sciences; Chile) and W. Le Goff (Foundation for Innovation in Cardiometabolism and Nutrition; France) for critically reading the manuscript and providing comments. The authors also thank all members of the Janssens Laboratory for the many discussions over the past years. This work was supported by a European Research Council (ERC) Consolidator Grant (DCRIDDLE-819314), Research Foundation – Flanders (FWO) Program Grants (G063218 and G050622N), FWO EOS Grant (G0G7318N) and FWO PhD Grant to V.B. (1134321N).
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Glossary
- Bone marrow-derived DCs
-
These cells are typically generated by differentiating bone marrow-derived cells in the presence of granulocyte–macrophage colony-stimulating factor (GM-CSF), leading to a heterogenous culture containing DC2-like cells (so-called GM-CSF DCs). Differentiation of bone marrow-derived cells in the presence of FMS-like tyrosine kinase 3 ligand (FLT3L) yields cDC1, cDC2 and pDCs that better resemble the in vivo counterparts (so-called Flt3 DCs), especially when co-cultured with fibroblasts expressing the Notch ligand Delta-like protein 1 (DLL1) (so-called Flt3 Notch DCs).
- Bridging channel
-
Specialized interfollicular regions in the spleen that connect the T zone with the red pulp.
- Cross-presenting
-
A process by which certain antigen-presenting cells can take up, process and present extracellular antigens on MHC class I molecules to CD8+ T cells. Normally, presentation on MHC class I molecules is associated with intracellular antigens.
- Cross-tolerance
-
A process whereby antigens are presented by dendritic cells (DCs) to CD8+ T cells in an immunosilent way, thereby inducing tolerance rather than priming of the T cell against the antigen.
- ‘Don’t eat me’ signal
-
Engagement of the signal regulatory protein a (SIRPα) on macrophages by binding to CD47 expressed on any target cell transmits a ‘don’t eat me’ signal, thereby preventing the engulfment of the CD47-expressing target cell by macrophages.
- Dynein–dynactin complex
-
Molecular motor complex consisting of cytoplasmic dynein that connects with its cofactor dynactin to move cargo (for example, late endosomes and lysosomes) on microtubules.
- Efferocytosis
-
The phagocytic removal of apoptotic cells.
- Kynurenine pathway
-
A metabolic process that has a crucial role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+) by consuming tryptophan and that produces immunoregulatory molecules, known as kynurenines.
- mTOR pathway
-
Central regulator of cell metabolism, thereby influencing cell growth and proliferation.
- OT-I cells
-
T cells derived from a transgenic mouse strain in which all T cells bear a transgenic TCR that recognizes ovalbumin residues 257–264 in the context of H2Kb and which are used to study the response of CD8+ T cells to antigen.
- Poly(I:C)
-
A synthetic analogue of double-stranded RNA that activates TLR3.
- Sumoylation
-
A post-translational modification whereby the small ubiquitin-like protein SUMO is coupled to a lysine on a target protein, thereby modulating several processes such as nuclear-cytosolic transport, transcriptional regulation or progression through the cell cycle.
- Tolerance
-
The mechanism by which the immune system prevents pathologic auto-reactivity against self and, thus, prevents autoimmune diseases. In extension, tolerance can be established against (innocuous) foreign antigens such as food-derived antigens (oral tolerance). An antigen is tolerated when immune cells such as antigen-specific T cells have been rendered inactive by either deletion (deletional tolerance), anergy or conversion to regulatory T cells after challenge. Memory is established and, therefore, true induction of tolerance can be defined as the absence of an immune reaction upon rechallenge with the same antigen, even when presented in infectious conditions.
- Unfolded protein response
-
(UPR). A highly conserved cellular stress response that is activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum.
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Bosteels, V., Janssens, S. Striking a balance: new perspectives on homeostatic dendritic cell maturation. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01079-5
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DOI: https://doi.org/10.1038/s41577-024-01079-5
