scholarly journals Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis

2015 ◽  
Vol 112 (47) ◽  
pp. E6535-E6543 ◽  
Author(s):  
Seong-Hye Hwang ◽  
Seung-Hyun Jung ◽  
Saseong Lee ◽  
Susanna Choi ◽  
Seung-Ah Yoo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
T Cell Activation ◽  
Copy Number ◽  
Immune Dysfunction ◽  
Receptor Activation ◽  
Specific Protein ◽  
T Cell Migration

Copy number variations (CNVs) have been implicated in human diseases. However, it remains unclear how they affect immune dysfunction and autoimmune diseases, including rheumatoid arthritis (RA). Here, we identified a novel leukocyte-specific protein 1 (LSP1) deletion variant for RA susceptibility located in 11p15.5. We replicated that the copy number of LSP1 gene is significantly lower in patients with RA, which correlates positively with LSP1 protein expression levels. Differentially expressed genes in Lsp1-deficient primary T cells represent cell motility and immune and cytokine responses. Functional assays demonstrated that LSP1, induced by T-cell receptor activation, negatively regulates T-cell migration by reducing ERK activation in vitro. In mice with T-cell–dependent chronic inflammation, loss of Lsp1 promotes migration of T cells into the target tissues as well as draining lymph nodes, exacerbating disease severity. Moreover, patients with RA show diminished expression of LSP1 in peripheral T cells with increased migratory capacity, suggesting that the defect in LSP1 signaling lowers the threshold for T-cell activation. To our knowledge, our work is the first to demonstrate how CNVs result in immune dysfunction and a disease phenotype. Particularly, our data highlight the importance of LSP1 CNVs and LSP1 insufficiency in the pathogenesis of RA and provide previously unidentified insights into the mechanisms underlying T-cell migration toward the inflamed synovium in RA.

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.

scholarly journals Optical Control of CD8+ T Cell Metabolism and Effector Functions

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrea M. Amitrano ◽  
Brandon J. Berry ◽  
Kihong Lim ◽  
Kyun-Do Kim ◽  
Richard E. Waugh ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
Membrane Potential ◽  
T Cell ◽  
T Cell Activation ◽  
Mitochondrial Membrane ◽  
Cell Activation ◽  
Cell Metabolism ◽  
Effector Function ◽  
T Cell Migration

Although cancer immunotherapy is effective against hematological malignancies, it is less effective against solid tumors due in part to significant metabolic challenges present in the tumor microenvironment (TME), where infiltrated CD8+ T cells face fierce competition with cancer cells for limited nutrients. Strong metabolic suppression in the TME is often associated with impaired T cell recruitment to the tumor site and hyporesponsive effector function via T cell exhaustion. Increasing evidence suggests that mitochondria play a key role in CD8+ T cell activation, effector function, and persistence in tumors. In this study, we showed that there was an increase in overall mitochondrial function, including mitochondrial mass and membrane potential, during both mouse and human CD8+ T cell activation. CD8+ T cell mitochondrial membrane potential was closely correlated with granzyme B and IFN-γ production, demonstrating the significance of mitochondria in effector T cell function. Additionally, activated CD8+ T cells that migrate on ICAM-1 and CXCL12 consumed significantly more oxygen than stationary CD8+ T cells. Inhibition of mitochondrial respiration decreased the velocity of CD8+ T cell migration, indicating the importance of mitochondrial metabolism in CD8+ T cell migration. Remote optical stimulation of CD8+ T cells that express our newly developed “OptoMito-On” successfully enhanced mitochondrial ATP production and improved overall CD8+ T cell migration and effector function. Our study provides new insight into the effect of the mitochondrial membrane potential on CD8+ T cell effector function and demonstrates the development of a novel optogenetic technique to remotely control T cell metabolism and effector function at the target tumor site with outstanding specificity and temporospatial resolution.

scholarly journals O22 Assessing the role of tendon T cell interactions in the development of chronicity in PsA

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Emma Garcia-Melchor ◽  
Giacomo Cafaro ◽  
Shatakshi Sood ◽  
Lindsay A. N Crowe ◽  
Michael McLean ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
T Cell Activation ◽  
Conditioned Media ◽  
Activated T Cells ◽  
Stromal Compartment ◽  
T Cell Migration ◽  
The Impact

Abstract Background Mechanical stress or damage is a well-known inducer of inflammation in both psoriasis and psoriatic arthritis (PsA). The occurrence of microtrauma at enthesial sites, areas subjected to high mechanic stress, could explain the development of local inflammation (enthesitis) that further extends to the synovial tissue through what it is known synovio-entheseal complex. Current treatment strategies mainly target the immune compartment, however there is growing evidence for the role of the stroma in the development of chronic inflammation. Increasing attention has focused on the interaction between the stroma and immune system and its role in the initiation/development of tissue inflammatory chronicity. Our hypothesis is that stromal cells in the tendon or tenocytes, once activated, are able to recruit and activate T cells into the tendon, which in turn may have an effect on the stroma, altogether leading to chronicity. Methods We assessed the effect of damage on healthy tenocytes after stimulation with conditioned media from tendon explants or IL-1β by qPCR and ELISA. A transwell membrane system was used to test the impact of conditioned media from tenocytes on T cell migration. T cells and tenocytes were co-cultured with or without the presence of a transwell membrane to quantify T cell activation (CD69 by FACS and IFN-γ by ELISA). Changes in gene expression on tenocytes after co-culture with activated T cells were analysed by qPCR. Results In the presence of damage, tenocytes upregulated inflammatory cytokines (IL-1β, IL-6), chemokines (IL-8, CCL2, CCL5, CXCL10) and adhesion molecules (ICAM-1). Of interest, we observed an upregulation of CCL20, both at transcript and protein level. Conditioned media from tenocytes induced T cell migration, especially after stimulation. Co-culture of tenocytes and T cells resulted in contact dependant activation of T cells. These activated T cells also had an effect on tenocytes, further upregulating the production of inflammatory mediators. Conclusion These results support the role of the tendon stromal compartment in the recruitment and activation of T cells, creating a feedback loop that could be involved in the maintenance of the inflammatory process and the development of chronicity in the context of PsA. Moreover, the production of CCL20 by tenocytes after damage could explain the preferential recruitment of Th17 or gamma delta T cells into the tendon. We are further investigating the mechanisms that govern this relationship that could be targeted therapeutically in the future. Disclosures E. Garcia-Melchor None. G. Cafaro None. S. Sood None. L.A.N. Crowe None. M. McLean None. I.B. McInnes None. M. Akbar None. N.L. Millar None.

The adaptor protein Lad associates with the G protein β subunit and mediates chemokine-dependent T-cell migration

Blood ◽  
2007 ◽  
Vol 109 (12) ◽  
pp. 5122-5128 ◽  
Author(s):  
Dongsu Park ◽  
Inyoung Park ◽  
Deogwon Lee ◽  
Young Bong Choi ◽  
Hyunsook Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
G Protein ◽  
T Cell Activation ◽  
Tyrosine Kinases ◽  
Ectopic Expression ◽  
Adaptor Protein ◽  
Β Subunit ◽  
T Cell Migration

Abstract Lck-interacting adaptor protein/Rlk/Itk-binding protein (Lad/RIBP) was previously identified as an adaptor protein involved in TCR-mediated T-cell activation. To elucidate the functions of Lad further, we here performed yeast 2-hybrid screening using Lad as bait and discovered that the G protein β subunit (Gβ) is a Lad-binding partner. Since the most well-known G protein–coupled receptor in T cells is the chemokine receptor, we investigated whether Lad is involved in chemokine signaling. We found that, upon chemokine treatment, Lad associated with Gβ in Jurkat T cells. Furthermore, ectopic expression of dominant-negative Lad or the reduction of endogenous Lad expression by siRNA impaired the chemokine-induced migration of T cells, indicating that Lad is required for chemokine-induced T-cell migration. Subsequent investigation of the signaling pathways revealed that, in response to chemokine, Lad associated with the tyrosine kinases Lck and Zap-70 and that Lad was essential for the activation of Zap-70. Moreover, Lad was required for the chemokine-dependent tyrosine phosphorylation of focal adhesion molecules that included Pyk2 and paxillin. Taken together, these data show that, upon chemokine stimulation, Lad acts as an adaptor protein that links the G protein β subunit to the tyrosine kinases Lck and Zap-70, thereby mediating T-cell migration.

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 Collagen Organization Does Not Influence T-Cell Distribution in Stroma of Human Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3648
Author(s):  
Eva-Maria Kamionka ◽  
Baifeng Qian ◽  
Wolfgang Gross ◽  
Frank Bergmann ◽  
Thilo Hackert ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Cell Distribution ◽  
Collagen Organization ◽  
T Cell Migration ◽  
Collagen Alignment

The dominant intrastromal T-cell infiltration in pancreatic cancer is mainly caused by the contact guidance through the excessive desmoplastic reaction and could represent one of the obstacles to an effective immune response in this tumor type. This study analyzed the collagen organization in normal and malignant pancreatic tissues as well as its influence on T-cell distribution in pancreatic cancer. Human pancreatic tissue was analyzed using immunofluorescence staining and multiphoton and SHG microscopy supported by multistep image processing. The influence of collagen alignment on activated T-cells was studied using 3D matrices and time-lapse microscopy. It was found that the stroma of malignant and normal pancreatic tissues was characterized by complex individual organization. T-cells were heterogeneously distributed in pancreatic cancer and there was no relationship between T-cell distribution and collagen organization. There was a difference in the angular orientation of collagen alignment in the peritumoral and tumor-cell-distant stroma regions in the pancreatic ductal adenocarcinoma tissue, but there was no correlation in the T-cell densities between these regions. The grade of collagen alignment did not influence the directionality of T-cell migration in the 3D collagen matrix. It can be concluded that differences in collagen organization do not change the spatial orientation of T-cell migration or influence stromal T-cell distribution in human pancreatic cancer. The results of the present study do not support the rationale of remodeling of stroma collagen organization for improvement of T-cell–tumor cell contact in pancreatic ductal adenocarcinoma.

scholarly journals Form and pattern of MUC1 expression on T cells activated in vivo or in vitro suggests a function in T-cell migration

Immunology ◽  
2003 ◽  
Vol 108 (1) ◽  
pp. 32-41 ◽  
Author(s):  
Isabel Correa ◽  
Tim Plunkett ◽  
Anda Vlad ◽  
Arron Mungul ◽  
Jessica Candelora-Kettel ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Muc1 Expression ◽  
T Cell Migration

scholarly journals Neuropilin-1 Expression on CD4 T Cells Is Atherogenic and Facilitates T Cell Migration to the Aorta in Atherosclerosis

2019 ◽  
Vol 203 (12) ◽  
pp. 3237-3246
Author(s):  
Dalia E. Gaddis ◽  
Lindsey E. Padgett ◽  
Runpei Wu ◽  
Catherine C. Hedrick
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Migration ◽  
Neuropilin 1

scholarly journals Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis

2007 ◽  
Vol 179 (4) ◽  
pp. 2609-2615 ◽  
Author(s):  
Won-Woo Lee ◽  
Zhi-Zhang Yang ◽  
Guangjin Li ◽  
Cornelia M. Weyand ◽  
Jörg J. Goronzy
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation

A Novel Role for CpG Oligonucleotides in Tumor Immunotherapy: CpG-ODN Induce Targeted Chemokine-Induced Lymphocyte Migration to the Peripheral Tissues in Humans.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1791-1791
Author(s):  
W. Nicholas Haining ◽  
Holger Kanzler ◽  
Jeffrey Davies ◽  
Linda Drury ◽  
Jeffrey Kutok ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Vaccine Adjuvant ◽  
Cpg Odn ◽  
Lymphocyte Migration ◽  
Peripheral Tissues ◽  
Gm Csf ◽  
T Cell Migration ◽  
Cell Counts

Abstract CpG ODN are being actively investigated as cancer vaccine adjuvants because they mature plasmacytoid dendritic cells (pDC) into potent antigen-presenting cells. In addition, TLR ligands induce a broad range of other immunologic effects in pDC including the secretion of interferon α (IFNa) and chemokines which alter lymphocyte migration. Whether these CpG-ODN driven TLR ligand signals enhance antigen specific Immunity and/or trafficking In humans Is presently unknown. We evaluated the efficacy of the CpG-ODN, 1018-ISS, as a vaccine adjuvant given with GM-CSF to induce T cell immunity in humans to the tumor antigen hTERT. Seventeen patients with advanced solid tumors were treated with 6 cycles of GM-CSF (x 3d), CpG-ODN (escalating from 3mg - 100mg × 1d) followed by a peptide vaccine (a CD8 epitope from hTERT), in a Phase I dose escalation study. Surprisingly, only one of seventeen patients showed a detectable hTERT-specific tetramer T cell response. However, the majority of patients developed marked peripheral blood (PB) lymphopenia after CpG-ODN. Time-course flow cytometry analysis of PB revealed that CD8, CD4, NK and B cell counts were all depressed immediately after CpG-ODN. The effect was transient, with normal counts returning after a week, suggesting that CpG-ODN induced alteration in cell migration rather than cell death. To find further evidence for altered migration we examined vaccine sites. Clinically, vaccine sites showed significant swelling/induration within hours of CpG-ODN administration, though none was dose-limiting. Immunohistochemistry of vaccine biopsies showed significant, perivascular accumulation of CD4 and CD8 T cells clustered around CD123+ pDC. Biopsies after CpG-ODN, but not after GM-CSF, showed a marked increase in expression of MxA, an interferon-inducible gene suggesting that the local activation of pDC with resultant IFNa secretion. qRT-PCR confirmed significant increases in a panel of IFNa-inducible genes in the PB after CpG-ODN, indicating a systemic effect of IFNa secretion. Lastly, we showed directly that CpG-ODN markedly increased the ability of purified pDC to induce T cell migration in an in vitro transwell assay, demonstrating that CpG-ODN stimulation of human pDC not only induces IFNa, but also other chemokines that are sufficient to chemoattract T cells. Our results show that CpG-ODN with GM-CSF may not be an effective adjuvant strategy for peptide tumor vaccines; but sequenced GM-CSF/CpG-ODN causes a chemokine response that effects T cell migration to the peripheral tissues. These findings suggest a role for CpG beyond that of a vaccine adjuvant as a mediator of lymphocyte migration, targeting immune responses to specific peripheral tissues. Therapeutic intratumoral GM-CSF/CpG-ODN injection could profoundly alter the local immunologic milieu, recruiting activated pDC and T cells to the tumor site, and tipping the balance towards an effective tumor-specific immune response.

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