Marginal zone B cells 'eaten' dendritic cells to 'hijack' their antigen-presenting function

Written by | Editor-in-Chief Qi | Effective immunity requires the coordination of multiple cells and molecules, some of which are part of the innate arm of the immune system's rapid response, such as those that make up the complement system and marginal zone (MZ) B cells
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Other types of molecules and cells are involved in the adaptive immune response that provides long-term protection
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These include conventional dendritic cells (cDCs) and major histocompatibility complex class II (MHC II) molecules
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The main role of MHCII is to bind to antigenic peptides encountered by antigen presenting cells (APCs), and the resulting peptide-loaded MHCII (pMHC II) complexes can be detected by CD4+ T cells on the cell membrane to initiate an adaptive immune response
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All APCs use the membrane ubiquitin ligase MARCH1 to ubiquitinate the cytoplasmic tail of MHCII, facilitating delivery of the pMHCII complex to lysosomes for degradation, thereby reducing its surface expression and half-life [1]
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The complement system contains more than 30 soluble and membrane proteins that undergo a cascade of activation upon encountering pathogens
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The key component is C3, which can be activated by the classical, lectin or alternative pathways
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Activated C3 binds covalently to carbohydrates on the bacterial cell wall and recruits other complement components
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In the uninfected condition, C3 can also bind to the plasma membrane of normal host cells, but can be recognized by surface receptors and serum proteases and cleaved into inactive forms C3dg and C3d, thereby preventing cell damage [2]
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While this approach allows the complement system to respond rapidly to infection, it is unknown whether this pathway plays other immunomodulatory roles at steady state
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Recently, the team of Jose A.
Villadangos and Justine D.
Mintern from the University of Melbourne published an article entitled Marginal zone B cells acquire dendritic cell functions by trogocytosis in the journal Science.
The researchers discovered that the inactive form of C3, C3dg It can bind to pMHC II on cDC, while marginal zone B cells recognize C3 through complement receptor 2 (CR2), phagocytose the MHC II-C3dg complex through trogocytosis and present it to T cells
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The highly specialized ubiquitin ligase MARCH1 in the plasma membrane of cDCs promotes its endocytosis and degradation by ubiquitinating MHC II-C3dg, thereby reducing the amount exposed on the surface of cDCs at steady state to prevent excessive depletion of cDCs
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The researchers found that the number of cDCs was significantly reduced in the spleen of March1–/– mice, while the number of cDCs in the lymph nodes and thymus was unchanged
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Interestingly, there is a group of cells in the spleen that highly express B cell receptor (BCR), B cell activation genes, and can detect cDCs surface proteins but do not transcribe the corresponding genes.
Further immunophenotype analysis confirmed this group of cells.
for MZ B cells
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Therefore, the authors suggest that MZ B cells may capture cDCs membrane proteins through cytognaization
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In vitro co-incubation experiments showed that B cells can phagocytose the fluorescently labeled plasma membrane of cDCs, and this effect is unidirectional and specific, because the transfer of B cell membrane proteins to cDCs, and the effect of B cells on macrophages, central Cytophagy of granulocytes,
etc.

In addition, "metastasis" in B-nucleated cDCs was enhanced by knockout of MARCH1, and the amount of two inactive forms of C3, a key complement component, C3dg or C3d, was increased by up to 20-fold on the surface of cDCs
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It should be noted that in mice lacking both March1 and MHC II, C3 components could hardly be detected on the surface of cDCs, indicating that MHC II and C3 may exist on the surface of cDCs in the form of a complex
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To test the above hypothesis, we detected the binding of MHC II to C3dg by co-immunoprecipitation experiments, but the MHC IIa–C3dg complex could not be detected if MHC II was deglycosylated with PNGase
F.

This binding is not characteristic of C57BL/6 mice, and the authors detected C3 expression in two other strains of mouse and human blood DCs
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In addition, two human donor DCs with impaired MHC II transcription also showed reduced expression levels of C3
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These findings suggest conservation of C3 binding to MHC II
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C3dg is a ligand for CR2 and is only expressed by B cells, with higher levels on the surface of MZ B cells
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The authors found that CR2-deficient B cells lost the ability to capture plasma membrane proteins from C3-bearing cDCs
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Similarly, mouse lymph nodes lacked MZ B cells, and almost no B cells were detected after cytophagocytosis of cDCs
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Not only that, but the authors also found that the decrease in the number of cDCs in the mouse spleen was consistent with the increase in the number of MZ B cells
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So do MZ B cells "hijack" the antigen-presenting function of cDCs by acquiring pMHC II complexes produced by cDCs through this cytognathic action? First, wild-type, MHC IIKRKI/KI (MHC II ubiquitinated lysine site mutated to arginine) and MHC IIKRKI/KI x C3-/- mice were treated with IEpep[3] and a control mAb, respectively Or immunization with Ag fused to a mAb that recognizes Clec9A (a cDC1 receptor), and presentation of IEpep bound to MHC II is detected with an antibody (YAe) that specifically recognizes this complex
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The authors found that immunization with a Clec9A-targeted mAb resulted in higher expression of IEPep in cDC1s in all mouse models, indicating that presentation of IEpep by cDC1 is independent of C3
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In contrast, epitope presentation by MZ B cells was C3-dependent, suggesting that C3-mediated cytognathism enables MZ B cells to present pMHC II complexes obtained from cDC1 rather than self-generated in vivo
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In addition, the authors also verified that this acquired pMHC II complex could be recognized by T cells through in vitro co-incubation experiments
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Figure 2.
MZ B cells "eaten" cDCs, acquire pMHC II-C3 complexes and present antigen to CD4+ T cells
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Collectively, this study describes how C3 and MHC II interact and how this interaction enables MZ B cells and cDCs to synergistically perform functions that they cannot perform alone
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At the same time, ubiquitination of MARCH1 acts as a balancing mechanism to counteract the deleterious consequences of MZ B cells cytophagy on cDCs
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Taken together, this mechanism expands the range of antigens that MZ B cells can present to T cells
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Original link: https://doi.
org/10.
1126/science.
abf7470 Publisher: Eleven References 1.
H.
Liu, JD Mintern, JA Villadangos, MARCH ligases in immunity.
Curr.
Opin.
Immunol.
58, 38– 43 (2019).
doi: 10.
1016/j.
coi.
2019.
03.
001; pmid: 310639342.
MK Pangburn, VP Ferreira, C.
Cortes, Discrimination between host and pathogens by the complement system.
Vaccine 26 (Suppl 8), I15– I21 (2008).
doi: 10.
1016/j.
vaccine.
2008.
11.
023; pmid: 193881593.
Rudensky AYu, S.
Rath, P.
Preston-Hurlburt, DB Murphy, CA Janeway Jr.
, On the complexity of self.
Nature 353 , 660–662 (1991).
doi: 10.
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