HIV-Bearing DCs Regulate T Cell Migration and Cell-Cell Contact Dynamics to Enhance Viral Spread

2020 ◽  
Author(s):  
Wan Hon Koh ◽  
Paul Lopez ◽  
Oluwaseun Ajibola ◽  
Roshan Parvarchian ◽  
Umar Mohammad ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Contact Dynamics ◽  
Cell Contact ◽  
Viral Spread ◽  
T Cell Migration ◽  
Cell Cell

scholarly journals HIV-Captured DCs Regulate T Cell Migration and Cell-Cell Contact Dynamics to Enhance Viral Spread

iScience ◽  
2020 ◽  
Vol 23 (8) ◽  
pp. 101427 ◽  
Author(s):  
Wan Hon Koh ◽  
Paul Lopez ◽  
Oluwaseun Ajibola ◽  
Roshan Parvarchian ◽  
Umar Mohammad ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Contact Dynamics ◽  
Cell Contact ◽  
Viral Spread ◽  
T Cell Migration ◽  
Cell Cell

scholarly journals HIV Infection Stabilizes Macrophage-T Cell Interactions To Promote Cell-Cell HIV Spread

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Paul Lopez ◽  
Wan Hon Koh ◽  
Ryan Hnatiuk ◽  
Thomas T. Murooka
Keyword(s):  
T Cells ◽  
T Cell ◽  
Live Cell Imaging ◽  
Cell Contact ◽  
Cell Infection ◽  
Cell Contacts ◽  
3 Dimensional ◽  
Viral Spread ◽  
Large Numbers ◽  
Cell Cell

ABSTRACTMacrophages are susceptible to HIV infection and play an important role in viral dissemination through cell-cell contacts with T cells. However, our current understanding of macrophage-to-T cell HIV transmission is derived from studies that do not consider the robust migration and cell-cell interaction dynamics between these cells. Here, we performed live-cell imaging studies in 3-dimensional (3D) collagen that allowed CD4+T cells to migrate and to locate and engage HIV-infected macrophages, modeling the dynamic aspects of thein situenvironment in which these contacts frequently occur. We show that HIV+macrophages form stable contacts with CD4+T cells that are facilitated by both gp120-CD4 and LFA-1–ICAM-1 interactions and that prolonged contacts are a prerequisite for efficient viral spread. LFA-1–ICAM-1 adhesive contacts function to restrain highly motile T cells, since their blockade substantially destabilized macrophage-T cell contacts, resulting in abnormal tethering events that reduced cell-cell viral spread. HIV-infected macrophages displayed strikingly elongated podosomal extensions that were dependent on Nef expression but were dispensable for stable cell-cell contact formation. Finally, we observed persistent T cell infection in dynamic monocyte-derived macrophage (MDM)-T cell cocultures in the presence of single high antiretroviral drug concentrations but achieved complete inhibition with combination therapy. Together, our data implicate macrophages as drivers of T cell infection by altering physiological MDM-T cell contact dynamics to access and restrain large numbers of susceptible, motile T cells within lymphoid tissues.IMPORTANCEOnce HIV enters the lymphoid organs, exponential viral replication in T cells ensues. Given the densely packed nature of these tissues, where infected and uninfected cells are in nearly constant contact with one another, efficient HIV spread is thought to occur through cell-cell contactsin vivo. However, this has not been formally demonstrated. In this study, we performed live-cell imaging studies within a 3-dimensional space to recapitulate the dynamic aspects of the lymphoid microenvironment and asked whether HIV can alter the morphology, migration capacity, and cell-cell contact behaviors between macrophages and T cells. We show that HIV-infected macrophages can engage T cells in stable contacts through binding of virus- and host-derived adhesive molecules and that stable macrophage-T cell contacts were required for high viral spread. Thus, HIV alters physiological macrophage-T cell interactions in order to access and restrain large numbers of susceptible, motile T cells, thereby playing an important role in HIV progression.

scholarly journals Extracellular vesicles from HTLV-1 infected cells modulate target cells and viral spread

Retrovirology ◽  
2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Daniel O. Pinto ◽  
Sarah Al Sharif ◽  
Gifty Mensah ◽  
Maria Cowen ◽  
Pooja Khatkar ◽  
...  
Keyword(s):  
T Cell ◽  
Extracellular Vesicles ◽  
Neurovascular Unit ◽  
Spastic Paraparesis ◽  
Host Protein ◽  
Cell Contact ◽  
Target Cells ◽  
Viral Spread ◽  
Human T Cell ◽  
Cell Cell

Abstract Background The Human T-cell Lymphotropic Virus Type-1 (HTLV-1) is a blood-borne pathogen and etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 has currently infected up to 10 million globally with highly endemic areas in Japan, Africa, the Caribbean and South America. We have previously shown that Extracellular Vesicles (EVs) enhance HTLV-1 transmission by promoting cell–cell contact. Results Here, we separated EVs into subpopulations using differential ultracentrifugation (DUC) at speeds of 2 k (2000×g), 10 k (10,000×g), and 100 k (100,000×g) from infected cell supernatants. Proteomic analysis revealed that EVs contain the highest viral/host protein abundance in the 2 k subpopulation (2 k > 10 k > 100 k). The 2 k and 10 k populations contained viral proteins (i.e., p19 and Tax), and autophagy proteins (i.e., LC3 and p62) suggesting presence of autophagosomes as well as core histones. Interestingly, the use of 2 k EVs in an angiogenesis assay (mesenchymal stem cells + endothelial cells) caused deterioration of vascular-like-tubules. Cells commonly associated with the neurovascular unit (i.e., astrocytes, neurons, and macrophages) in the blood–brain barrier (BBB) showed that HTLV-1 EVs may induce expression of cytokines involved in migration (i.e., IL-8; 100 k > 2 k > 10 k) from astrocytes and monocyte-derived macrophages (i.e., IL-8; 2 k > 10 k). Finally, we found that EVs were able to promote cell–cell contact and viral transmission in monocytic cell-derived dendritic cell. The EVs from both 2 k and 10 k increased HTLV-1 spread in a humanized mouse model, as evidenced by an increase in proviral DNA and RNA in the Blood, Lymph Node, and Spleen. Conclusions Altogether, these data suggest that various EV subpopulations induce cytokine expression, tissue damage, and viral spread.

scholarly journals Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T cell migration into tumors

2021 ◽  
Author(s):  
Paulina Akeus ◽  
Louis Szeponik ◽  
Veronica Langenes ◽  
Viktoria Karlsson ◽  
Patrik Sundström ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Regulatory T Cells ◽  
Neutral Sphingomyelinase ◽  
T Cell Migration

scholarly journals Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease

2021 ◽  
pp. annrheumdis-2020-219335
Author(s):  
Emma Garcia-Melchor ◽  
Giacomo Cafaro ◽  
Lucy MacDonald ◽  
Lindsay A N Crowe ◽  
Shatakshi Sood ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
T Cell Activation ◽  
Cell Activation ◽  
Conditioned Media ◽  
Tissue Remodelling ◽  
Activated T Cells ◽  
T Cell Migration

ObjectivesIncreasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation.MethodsT cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes.ResultsSignificant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte–T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio.ConclusionsInteraction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.

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