Regulatory T Cells from Colon Cancer Patients Inhibit Effector T-cell Migration through an Adenosine-Dependent Mechanism

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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Behavior of Circulating CD4+CD25+Foxp3+ Regulatory T Cells in Colon Cancer Patients Undergoing Surgery

Journal of Clinical Immunology ◽

10.1007/s10875-011-9585-8 ◽

2011 ◽

Vol 31 (6) ◽

pp. 1095-1104 ◽

Cited By ~ 25

Author(s):

Ausilia Sellitto ◽

Gennaro Galizia ◽

Umberto De Fanis ◽

Eva Lieto ◽

Anna Zamboli ◽

...

Keyword(s):

Colon Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Cancer Patients

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

Cancers ◽

10.3390/cancers13153648 ◽

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.

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The cannabinoid WIN55212‐2 suppresses effector T cell responses and promotes regulatory T cells in human tonsils

Allergy ◽

10.1111/all.15160 ◽

2021 ◽

Author(s):

Alba Angelina ◽

Mario Pérez‐Diego ◽

Angel Maldonado ◽

Beate Rückert ◽

Mübeccel Akdis ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Responses ◽

Effector T Cell ◽

Cell Responses

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Increased frequencies of CD4+CD25high regulatory T cells in acute dengue infection

Journal of Experimental Medicine ◽

10.1084/jem.20061381 ◽

2007 ◽

Vol 204 (5) ◽

pp. 979-985 ◽

Cited By ~ 95

Author(s):

Kerstin Lühn ◽

Cameron P. Simmons ◽

Edward Moran ◽

Nguyen Thi Phuong Dung ◽

Tran Nguyen Bich Chau ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Severe Disease ◽

Acute Infection ◽

Dengue Infection ◽

Hemorrhagic Fever ◽

Severe Dengue ◽

Effector T Cell ◽

Cell Effector

Dengue virus infection is an increasingly important tropical disease, causing 100 million cases each year. Symptoms range from mild febrile illness to severe hemorrhagic fever. The pathogenesis is incompletely understood, but immunopathology is thought to play a part, with antibody-dependent enhancement and massive immune activation of T cells and monocytes/macrophages leading to a disproportionate production of proinflammatory cytokines. We sought to investigate whether a defective population of regulatory T cells (T reg cells) could be contributing to immunopathology in severe dengue disease. CD4+CD25highFoxP3+ T reg cells of patients with acute dengue infection of different severities showed a conventional phenotype. Unexpectedly, their capacity to suppress T cell proliferation and to secrete interleukin-10 was not altered. Moreover, T reg cells suppressed the production of vasoactive cytokines after dengue-specific stimulation. Furthermore, T reg cell frequencies and also T reg cell/effector T cell ratios were increased in patients with acute infection. A strong indication that a relative rise of T reg cell/effector T cell ratios is beneficial for disease outcome comes from patients with mild disease in which this ratio is significantly increased (P < 0.0001) in contrast to severe cases (P = 0.2145). We conclude that although T reg cells expand and function normally in acute dengue infection, their relative frequencies are insufficient to control the immunopathology of severe disease.

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