Exhausted mature dendritic cells exhibit a slower and less persistent random motility but retain chemotaxis against CCL19

Abstract Langerhans cells (LCs) are immature dendritic cells (DCs) that capture antigen in peripheral tissues and migrate to draining lymph nodes, where they reside in the paracortex as interdigitating dendritic cells (IDCs). We studied the effects of simian immunodeficiency virus (SIV) on LCs and IDCs during different stages of infection in monkeys. LCs isolated from monkeys with acute SIV infection or acquired immunodeficiency syndrome (AIDS) underwent normal maturation in vitro, including a switch in chemokine receptor expression from CCR5 to CXCR4 and CCR7. LCs migrated normally from skin in response to contact sensitization in monkeys with acute SIV infection. In contrast, LC migration from skin was markedly impaired during AIDS, associated with a reduction in antigen-bearing DCs in draining lymph nodes. Lymph node IDCs were increased in proportion during acute SIV infection and had an activated phenotype, whereas during AIDS IDCs had significantly lower expression of CD40 and the activation marker CD83. IDCs from monkeys with AIDS were refractory to stimulation with CD40L, demonstrating a functional consequence of decreased CD40 expression. SIV-infected DCs were not identified in lymph nodes or skin of monkeys with AIDS, suggesting an indirect effect of infection on DC populations in vivo. These data indicate that DCs are mobilized to lymph nodes during acute SIV infection, but that during AIDS this process is suppressed, with LC migration and IDC activation being impaired. We conclude that disruption of DC homeostasis may play a role in immunopathology induced by human immunodeficiency virus and suggest that therapeutic strategies targeting DCs may have limited efficacy during AIDS.

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Bone marrow dendritic cell progenitors sense pathogens via Toll-like receptors and subsequently migrate to inflamed lymph nodes

Blood ◽

10.1182/blood-2011-03-344960 ◽

2011 ◽

Vol 118 (18) ◽

pp. 4829-4840 ◽

Cited By ~ 43

Author(s):

Michael A. Schmid ◽

Hitoshi Takizawa ◽

Dior R. Baumjohann ◽

Yasuyuki Saito ◽

Markus G. Manz

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Dendritic Cell ◽

Lymph Nodes ◽

Proliferative Activity ◽

Toll Like Receptors ◽

Peripheral Tissues ◽

Tlr Agonists ◽

Lineage Differentiation ◽

Pathogen Recognition Receptors

Abstract Common dendritic cell progenitors (CDPs) in the bone marrow (BM) regenerate dendritic cells (DCs) in lymphoid and nonlymphoid tissues. How the dissemination of progenitor-derived DCs to peripheral tissues is regulated on need remains elusive. Microbes are sensed by pathogen recognition receptors such as Toll-like receptors (TLRs). We found that CDPs in the BM express TLR2, TLR4, and TLR9. On TLR stimulation, CDPs down-regulated CXCR4, the nonredundant chemokine receptor for their BM retention, up-regulated CCR7, and migrated to lymph nodes (LNs). When TLR agonists were injected locally, CDPs preferentially gave rise to DCs in inflamed LNs in expense of noninflamed LNs and the BM, but they did not alter their lineage differentiation and proliferative activity. Consequently, BM DC progenitors can sense TLR agonists and, via regulation of CXCR4 and CCR7, support the replenishment of DCs in reactive LNs. This mechanism likely developed to support DC homeostasis on specific need at sites of inflammation.

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Characterization of resident and migratory dendritic cells in human lymph nodes

Journal of Experimental Medicine ◽

10.1084/jem.20111457 ◽

2012 ◽

Vol 209 (4) ◽

pp. 653-660 ◽

Cited By ~ 214

Author(s):

Elodie Segura ◽

Jenny Valladeau-Guilemond ◽

Marie-Hélène Donnadieu ◽

Xavier Sastre-Garau ◽

Vassili Soumelis ◽

...

Keyword(s):

Dendritic Cells ◽

Lymph Nodes ◽

T Cell Activation ◽

Cell Activation ◽

Peripheral Tissues ◽

Th2 Polarization ◽

Th1 And Th2 Cytokines ◽

Two Populations

Dendritic cells (DCs) initiate adaptive immune responses in lymph nodes (LNs). In mice, LN DCs can be divided into resident and tissue-derived populations, the latter of which migrate from the peripheral tissues. In humans, different subsets of DCs have been identified in the blood, spleen, and skin, but less is known about populations of resident and migratory tissue-derived DCs in LNs. We have analyzed DCs in human LNs and identified two populations of resident DCs that are present in all LNs analyzed, as well as in the spleen and tonsil, and correspond to the two known blood DC subtypes. We also identify three main populations of skin-derived migratory DCs that are present only in skin-draining LNs and correspond to the DC subsets found in the skin. Resident DCs subsets induce both Th1 and Th2 cytokines in naive allogeneic T lymphocytes, whereas the corresponding blood subsets failed to induce efficient Th2 polarization. LN-resident DCs also cross-present antigen without in vitro activation, whereas blood DCs fail to do so. Among migratory DCs, one subset was poor at both CD4+ and CD8+ T cell activation, whereas the other subsets induced only Th2 polarization. We conclude that in humans, skin-draining LNs host both resident and migratory DC subsets with distinct functional abilities.

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Exhausted mature dendritic cells exhibit a slower and less persistent random motility but retain chemotaxis against CCL19

10.1101/2021.10.11.463881 ◽

2021 ◽

Author(s):

Yongjun Choi ◽

Vijaya Sunkara ◽

Yeojin Lee ◽

Yoon-Kyoung Cho

Keyword(s):

Dendritic Cells ◽

Space Exploration ◽

Cellular Migration ◽

Migration Behavior ◽

Cellular Motility ◽

Random Motility ◽

Peripheral Tissues ◽

Inflammatory Conditions ◽

Effective Immune Response ◽

Speed Fluctuation

Dendritic cells (DCs), which are immune sentinels in the peripheral tissues, play a number of roles, including patrolling for pathogens, internalising antigens, transporting antigens to the lymph nodes (LNs), interacting with T cells, and secreting cytokines. The well-coordinated migration of DCs under various immunological or inflammatory conditions is therefore essential to ensure an effective immune response. Upon maturation, DCs migrate faster and more persistently than immature DCs (iDCs), which is believed to facilitate CCR7-dependent chemotaxis. It has been reported that lipopolysaccharide-activated DCs produce IL-12 only transiently, and become resistant to further stimulation through exhaustion. However, little is known about the influence of DC exhaustion on cellular motility. Here, we studied the cellular migration of exhausted DCs in tissue-mimicked confined environments. We found that the speed of exhausted matured DCs (xmDCs) decreased significantly compared to active matured DCs (amDCs) and iDCs. In contrast, the speed fluctuation increased compared to that of amDCs and was similar to that of iDCs. In addition, the diffusivity of the xmDCs was significantly lower than that of the amDCs, which implies that DC exhaustion reduces the space exploration ability. Interestingly, CCR7-dependent chemotaxis against CCL19 in xmDCs was not considerably different from that observed in amDCs. Taken together, we report a unique intrinsic cell migration behavior of xmDCs, which exhibit a slower, less persistent, and less diffusive random motility, which results in the DCs remaining at the site of infection, although a well-preserved CCR7-dependent chemotactic motility is maintained.

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