Structure and Immune Function of Afferent Lymphatics and Their Mechanistic Contribution to Dendritic Cell and T Cell Trafficking

Arasa, Jorge; Collado-Díaz, Víctor; Halin, Cornelia

doi:10.3390/cells10051269

Cited by 29 publications

(24 citation statements)

References 192 publications

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“…Immune cell migration is an important function of the lymphatic system and is dependent on the lymphatic channels’ structural integrity and LEC expression of chemokines and adhesion molecules ( Hampton and Chtanova, 2019 ; Arasa et al, 2021 ). We found that aging markedly decreased trafficking of DCs from the periphery to the draining LN.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Changes in Aged Skin Lymphatic Vessels

et al. 2022

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Lymphatic structure and function play a critical role in fluid transport, antigen delivery, and immune homeostasis. A dysfunctional lymphatic system is associated with chronic low-grade inflammation of peripheral tissues, poor immune responses, and recurrent infections, which are also hallmarks of aging pathology. Previous studies have shown that aging impairs lymphatic structure and function in a variety of organ systems, including the intestines and central nervous system. However, previous studies are mostly limited to qualitative analysis of lymphatic structural changes and quantification of intestinal collecting vessel contractile function. It is not clear whether decreased lymphatic function contributes to pathological conditions related to aging, nor how it affects the skin immune microenvironment. Further, the effects of aging on skin initial and collecting lymphatic vessels, dendritic cell (DC) migration, cutaneous lymphatic pumping, and VEGFR-3 signaling in lymphatic endothelial cells (LECs) have not been quantitatively analyzed. Here, using fluorescent immunohistochemistry and flow cytometry, we confirm that aging decreases skin initial and collecting lymphatic vessel density. Indocyanine green (ICG) lymphangiography and DC migration assays confirm that aging decreases both fluid pumping and cell migration via lymphatic vessels. At the cellular level, aging causes decreased VEGFR-3 signaling, leading to increased LEC apoptosis and senescence. Finally, we determined that aging causes decreased lymphatic production of chemokines and alters LEC expression of junctional and adhesion molecules. This in turn leads to increased peri-lymphatic inflammation and nitrosative stress that might contribute to aging pathology in a feed-forward manner. Taken together, our study, in addition to quantitatively corroborating previous findings, suggests diverse mechanisms that contribute to lymphatic dysfunction in aging that in turn exacerbate the pathology of aging in a feed-forward manner.

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Section: Discussionmentioning

confidence: 99%

Structural and Functional Changes in Aged Skin Lymphatic Vessels

et al. 2022

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“…In other cases, cells appeared to already be detached, rounded up, and in flow within the red pulp at the time of reaching a large vessel (movie S4). Like intravascular DCs in dermal lymphatics (32), intravascular cDC2s often continued to migrate for a period of time before being carried away into the blood flow (Fig. 5G and movies S3 and S4).…”

Section: Cd97 Pathway Restrains Splenic Cdc2 Migrationmentioning

confidence: 97%

CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells

Liu

Duan

Rodda

et al. 2022

Science

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Dendritic cells (DCs) are crucial for initiating adaptive immune responses. However, the factors that control DC positioning and homeostasis are incompletely understood. We found that type-2 conventional DCs (cDC2s) in the spleen depend on Gα 13 and adhesion G protein–coupled receptor family member-E5 (Adgre5, or CD97) for positioning in blood-exposed locations. CD97 function required its autoproteolytic cleavage. CD55 is a CD97 ligand, and cDC2 interaction with CD55-expressing red blood cells (RBCs) under shear stress conditions caused extraction of the regulatory CD97 N-terminal fragment. Deficiency in CD55-CD97 signaling led to loss of splenic cDC2s into the circulation and defective lymphocyte responses to blood-borne antigens. Thus, CD97 mechanosensing of RBCs establishes a migration and gene expression program that optimizes the antigen capture and presentation functions of splenic cDC2s.

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“…The study also showed that the HA content within the glycocalyx was upregulated for mature DCs compared to immature DCs, and consequently, that the presence of HA glycocalyx is necessary for trafficking over the lymphatic endothelium and allowing crawling along the endothelia ( 41 , 42 ). This aspect becomes crucial considering that long-lived MHC-dependent T cell–DC interactions occur on the luminal side of afferent lymphatic capillaries ( 43 , 44 ).…”

Section: Antigen Scanning Entities: Microvilli Of T Cellsmentioning

confidence: 99%

Mechanosurveillance: Tiptoeing T Cells

et al. 2022

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Efficient scanning of tissue that T cells encounter during their migratory life is pivotal to protective adaptive immunity. In fact, T cells can detect even a single antigenic peptide/MHC complex (pMHC) among thousands of structurally similar yet non-stimulatory endogenous pMHCs on the surface of antigen-presenting cells (APCs) or target cells. Of note, the glycocalyx of target cells, being composed of proteoglycans and bulky proteins, is bound to affect and even modulate antigen recognition by posing as a physical barrier. T cell-resident microvilli are actin-rich membrane protrusions that puncture through such barriers and thereby actively place the considerably smaller T-cell antigen receptors (TCRs) in close enough proximity to APC-presented pMHCs so that productive interactions may occur efficiently yet under force. We here review our current understanding of how the plasticity of T-cell microvilli and physicochemical properties of the glycocalyx may affect early events in T-cell activation. We assess insights gained from studies on T-cell plasma membrane ultrastructure and provide an update on current efforts to integrate biophysical aspects such as the amplitude and directionality of TCR-imposed mechanical forces and the distribution and lateral mobility of plasma membrane-resident signaling molecules into a more comprehensive view on sensitized T-cell antigen recognition.

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Structure and Immune Function of Afferent Lymphatics and Their Mechanistic Contribution to Dendritic Cell and T Cell Trafficking

Cited by 29 publications

References 192 publications

Structural and Functional Changes in Aged Skin Lymphatic Vessels

Structural and Functional Changes in Aged Skin Lymphatic Vessels

CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells

Mechanosurveillance: Tiptoeing T Cells

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