scholarly journals CD8+ T cells inhibit metastasis and CXCL4 regulates its function

2021 ◽  
Author(s):  
Robiya Joseph ◽  
Rama Soundararajan ◽  
Suhas Vasaikar ◽  
Fei Yang ◽  
Kendra L. Allton ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Cell Function ◽  
Tumour Progression ◽  
Suppressor Cells ◽  
Cancer Data ◽  
T Cell Function ◽  
Mouse Tumour

Abstract Background The mechanism by which immune cells regulate metastasis is unclear. Understanding the role of immune cells in metastasis will guide the development of treatments improving patient survival. Methods We used syngeneic orthotopic mouse tumour models (wild-type, NOD/scid and Nude), employed knockout (CD8 and CD4) models and administered CXCL4. Tumours and lungs were analysed for cancer cells by bioluminescence, and circulating tumour cells were isolated from blood. Immunohistochemistry on the mouse tumours was performed to confirm cell type, and on a tissue microarray with 180 TNBCs for human relevance. TCGA data from over 10,000 patients were analysed as well. Results We reveal that intratumoral immune infiltration differs between metastatic and non-metastatic tumours. The non-metastatic tumours harbour high levels of CD8+ T cells and low levels of platelets, which is reverse in metastatic tumours. During tumour progression, platelets and CXCL4 induce differentiation of monocytes into myeloid-derived suppressor cells (MDSCs), which inhibit CD8+ T-cell function. TCGA pan-cancer data confirmed that CD8lowPlatelethigh patients have a significantly lower survival probability compared to CD8highPlateletlow. Conclusions CD8+ T cells inhibit metastasis. When the balance between CD8+ T cells and platelets is disrupted, platelets produce CXCL4, which induces MDSCs thereby inhibiting the CD8+ T-cell function.

scholarly journals Combined Deficiency of p50 and cRel in CD4+ T Cells Reveals an Essential Requirement for Nuclear Factor κB in Regulating Mature T Cell Survival and In Vivo Function

2003 ◽  
Vol 197 (7) ◽  
pp. 861-874 ◽  
Author(s):  
Ye Zheng ◽  
Monika Vig ◽  
Jesse Lyons ◽  
Luk Van Parijs ◽  
Amer A. Beg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Nuclear Factor ◽  
T Cell Function ◽  
T Cell Survival

Signaling pathways involved in regulating T cell proliferation and survival are not well understood. Here we have investigated a possible role of the nuclear factor (NF)-κB pathway in regulating mature T cell function by using CD4+ T cells from p50−/− cRel−/− mice, which exhibit virtually no inducible κB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-κB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-κB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-κB–inducing IκB kinase β showed that NF-κB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-κB in both IL-2 and Akt-induced survival pathways. In vivo, p50−/− cRel−/− mice showed impaired superantigen-induced T cell responses as well as decreased numbers of effector/memory and regulatory CD4+ T cells. These findings provide the first demonstration of a role for NF-κB proteins in regulating T cell function in vivo and establish a critically important function of NF-κB in TCR-induced regulation of survival.

scholarly journals Fine-Tuning of Regulatory T Cell Function: The Role of Calcium Signals and Naive Regulatory T Cells for Regulatory T Cell Deficiency in Multiple Sclerosis

2013 ◽  
Vol 190 (10) ◽  
pp. 4965-4970 ◽  
Author(s):  
Alexander Schwarz ◽  
Marijana Schumacher ◽  
Daniel Pfaff ◽  
Kai Schumacher ◽  
Sven Jarius ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Cell Function ◽  
Fine Tuning ◽  
Calcium Signals ◽  
T Cell Function

Regulation Of T-ALL Migration By PKCθ and Carma1

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4987-4987
Author(s):  
Sreenivasa Rao Oruganti ◽  
Savannah Krebsbach ◽  
Francois Asperti-Boursin ◽  
Sumit Patel ◽  
Stuart S. Winter ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Chemokine Receptor ◽  
Cell Function ◽  
Leukemic Cells ◽  
T Cell Function ◽  
Tumor Load ◽  
Leukemia Development

Abstract Acute lymphoblastic leukemia (ALL) is one of the most commonly seen childhood lymphomas, and can arise from the T or B cell lineage (T-ALL or B-ALL respectively). T-ALL patients have almost 80% cure rate, however relapse in central nervous system (CNS) remains a major therapeutic challenge. Recently it has been shown that a chemokine receptor CCR7 is an essential regulator of T-ALL cell infiltration into the CNS. CCR7 is a homeostatic chemokine receptor that controls the homing of cells to lymph nodes, including naïve T cells, dendritic cells, and lymphoma cells. The ligands for CCR7, CCL19 and CCL21, are expressed by stromal cells in the secondary lymphoid organs. CCL21 and CCL19 function as chemoattractants for T and B lymphocytes expressing CCR7. Defects in either CCR7 or its ligands impairs lymphocyte migration. Aberrant CCR7 expression has been associated with certain cancers such as gastric cancers, breast cancers and head and neck cancers and been linked to pro-survival and invasive pathways. While CCR7 controls the migration of naïve T cells and T-ALL leukemic cells, little is known about the signaling pathways downstream of CCR7. Numerous studies have demonstrated the importance of Protein Kinase C θ (PKCθ) in normal T cell function as well as T-ALL. PKCθ regulates NF-κB by interaction with a complex of proteins including CARMA1, BCL10, and MALT1, which all function together to activate NF-κB upon T cell receptor ligation. In addition to being crucial for normal T cell activation, PKCθ has also been shown to be important in T-ALL induction in a mouse model of T-ALL. While PKCθ is clearly important in multiple aspects of T cell function, nothing is known about the potential role of PKCθ in controlling migration of T cells, including leukemic cells. We have established xenograft model of T-ALL, where we could assess the engraftment of T-ALL tumors into the NOD/SCID/IL2Rγ2 immunodeficient mice. Using T-ALL cells that express luciferase, we can image tumor load using the IVIS imaging system. Here we show that animals receiving T-ALL cells lacking CARMA1 show a significant  delay in timing of leukemia development and longer overall survival compared to animals receiving Wild type T-ALL cells (n=25, P value < 0.0001). In contrast, we did not observe any difference in timing of leukemia development or overall survival of the mice injected with WT or T-ALL cells that lack PKCθ. We hypothesize that the longer survival of animals injected with CARMA1-knockdown T-ALL cells results from lower tumor burden in the brain. Currently we are analyzing different organs including brain using immunohistochemistry to determine whether the differences in the migration and tumor load account for the differences between WT and CARMA1-knockdown T-ALL cells. As an additional control, we will confirm the role of PKCθ and CARMA1 in T-ALL migration by inducing T-ALL with NOTCH-1 mutant in mice knocked out for CARMA1 and PKCθ. These results demonstrate for the first time that CARMA1 may play an important role in T-ALL induction and possibly migration to the CNS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The specific binding of Listeria monocytogenes-immune T lymphocytes to macrophages. I. Quantitation and role of H-2 gene products.

1979 ◽  
Vol 150 (5) ◽  
pp. 1143-1160 ◽  
Author(s):  
K Ziegler ◽  
E R Unanue
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Cell Function ◽  
Specific Binding ◽  
Physical Interaction ◽  
Gene Products ◽  
Gene Complex ◽  
T Cell Function

A system was developed to study the binding of Listeria monocytogenes-specific T cells to L. monocytogenes-pulsed macrophages as an analogue of the initial phase of T-cell activation: antigen recognition. Specific binding, demonstrable after a brief (1 h) contact, was quantitated by the depletion of L. monocytogenes-specific T-cell activity in the cells nonadherent to L. monocytogenes-pulsed macrophage monolayers. L. monocytogenes-specific T-cell function was measured by its ability to activate L. monocytogenes-pulsed macrophages, both to secrete a protein mitogenic for thymocytes and to effect nonspecific tumoricidal activity. These manifestations of T-cell function are known to be regulated by products of I region of the H-2 gene complex. Studies designed to determine the role of H-2 gene products in specific T-cell-macrophage binding have revealed the following. T cells bind specifically to syngeneic macrophages and poorly to allogeneic macrophages. The binding ability appears to map to the K end of the H-2 gene complex (K through I-E). At least two distinct populations of B6AF1 T cells with binding avidity for L. monocytogenes presented on parental macrophages can be identified. Finally, the binding of a given parental-reactive B6AF1 T-cell clone can be specifically inhibited by pretreatment of the antigen-pulsed B6AF1 binding macrophage with anti-H-2 (anti-Ia) antibodies reactive with the appropriate parental haplotype. These results strongly suggest that H-2 gene products play a direct role in mediating the specific binding of T cells to macrophages and imply that the antigen-dependent physical interaction between T cells and macrophages is the initial, and determining, event in some forms of H-2 gene control of immune reactivity.

scholarly journals Small molecule AZD4635 inhibitor of A2AR signaling rescues immune cell function including CD103+ dendritic cells enhancing anti-tumor immunity

2020 ◽  
Vol 8 (2) ◽  
pp. e000417 ◽  
Author(s):  
Alexandra Borodovsky ◽  
Christine M Barbon ◽  
Yanjun Wang ◽  
Minwei Ye ◽  
Laura Prickett ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
Small Molecule ◽  
Immune Cells ◽  
Antitumor Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
T Cell Function ◽  
Adenosine Signaling

Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to escape detection by the immune system. Adenosine signaling through the adenosine 2A receptor (A2AR) on immune cells elicits a range of immunosuppressive effects which promote tumor growth and limit the efficacy of immune checkpoint inhibitors. Preclinical data with A2AR inhibitors have demonstrated tumor regressions in mouse models by rescuing T cell function; however, the mechanism and role on other immune cells has not been fully elucidated.MethodsWe report here the development of a small molecule A2AR inhibitor including characterization of binding and inhibition of A2AR function with varying amounts of a stable version of adenosine. Functional activity was tested in both mouse and human T cells and dendritic cells (DCs) in in vitro assays to understand the intrinsic role on each cell type. The role of adenosine and A2AR inhibition was tested in DC differentiation assays as well as co-culture assays to access the cross-priming function of DCs. Syngeneic models were used to assess tumor growth alone and in combination with alphaprogrammed death-ligand 1 (αPD-L1). Immunophenotyping by flow cytometry was performed to examine global immune cell changes upon A2AR inhibition.ResultsWe provide the first report of AZD4635, a novel small molecule A2AR antagonist which inhibits downstream signaling and increases T cell function as well as a novel mechanism of enhancing antigen presentation by CD103+ DCs. The role of antigen presentation by DCs, particularly CD103+ DCs, is critical to drive antitumor immunity providing rational to combine a priming agent AZD4635 with check point blockade. We find adenosine impairs the maturation and antigen presentation function of CD103+ DCs. We show in multiple syngeneic mouse tumor models that treatment of AZD4635 alone and in combination with αPD-L1 led to decreased tumor volume correlating with enhanced CD103+ function and T cell response. We extend these studies into human DCs to show that adenosine promotes a tolerogenic phenotype that can be reversed with AZD4635 restoring antigen-specific T cell activation. Our results support the novel role of adenosine signaling as an intrinsic negative regulator of CD103+ DCs maturation and priming. We show that potent inhibition of A2AR with AZD4635 reduces tumor burden and enhances antitumor immunity. This unique mechanism of action in CD103+ DCs may contribute to clinical responses as AZD4635 is being evaluated in clinical trials with IMFINZI (durvalumab, αPD-L1) in patients with solid malignancies.ConclusionWe provide evidence implicating suppression of adaptive and innate immunity by adenosine as a mechanism for immune evasion by tumors. Inhibition of adenosine signaling through selective small molecule inhibition of A2AR using AZD4635 restores T cell function via an internal mechanism as well as tumor antigen cross-presentation by CD103+ DCs resulting in antitumor immunity.

scholarly journals Does CD1a Expression Influence T Cell Function in Patients With Langerhans Cell Histiocytosis?

2021 ◽  
Vol 12 ◽  
Author(s):  
Jenée Mitchell ◽  
George Kannourakis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Langerhans Cell Histiocytosis ◽  
Inflammatory Infiltrate ◽  
Cell Function ◽  
Langerhans Cell ◽  
Myeloid Lineage ◽  
Disease States ◽  
T Cell Function

Langerhans cell histiocytosis lesions are characterized by CD1a+ myeloid lineage LCH cells and an inflammatory infiltrate of cytokines and immune cells, including T cells. T cells that recognize CD1a may be implicated in the pathology of many disease states including cancer and autoimmunity but have not been studied in the context of LCH despite the expression of CD1a by LCH cells. In this perspective article, we discuss the expression of CD1a by LCH cells, and we explore the potential for T cells that recognize CD1a to be involved in LCH pathogenesis.

scholarly journals Mir-181c Modulates T Cell Function By Regulating the Expression of BRK1

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 132-132
Author(s):  
Shok Ping Lim ◽  
Donal McLornan ◽  
Nikolaos Ioannou ◽  
David Darling ◽  
Alan G. Ramsay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Synapse Formation ◽  
Cell Function ◽  
Immune Synapse ◽  
T Cell Function ◽  
Lamellipodia Formation

Abstract Introduction MicroRNAs (miRNAs) are short endogenous non-coding RNAs consisting of 18-25 nucleotides in length which influence gene expression and play pivotal roles in a diverse range of cellular processes. Aberrant miRNA expression has been implicated in a variety of cancers, including haematological malignancies. The miR-181 family plays a crucial role in haematopoiesis, including megakaryocytic, erythroid and myeloid differentiation and both B and T cell development and differentiation. We therefore focused our study on validating novel downstream targets of miR-181. Methods A novel functional assay utilising an optimised 3'UTR enriched library and a dual selection strategy (Gäken et al., 2012) was performed to identify biologically relevant targets of miR-181c. BRK1 (BRICK1, SCAR/WAVE Actin Nucleating Complex Subunit) was identified as a potential target and validation was performed by quantitative real time PCR and western blot analysis. Given the potential role of BRK1 in the Wiskott-Aldrich Syndrome Protein Family Verprolin-Homologous Protein-2 (WAVE2) complex and actin polymerisation in T cells, we investigated the influence of the miR-181c-BRK1 axis on T cell function. Knockdown of BRK1, using short hairpin RNA (shRNA) lentiviral vectors, and overexpression of miR-181c, via transfection with miR-181c expression vectors, were performed in Jurkat and primary T cells. T cell activation was examined by measurement of CD69 and CD154 expression and actin polymerisation was quantified by total cellular F-actin content. Immune synapse formation was studied by conjugate formation between T cells and antigen-pulsed B cells. Lastly, lamellipodia formation was investigated by assessing the ability of T cells to spread on anti-CD3 coated slides. Results Target genes downregulated by miR-181c were identified. One such target was BRK1, a component of the WAVE2 complex that has been shown to play a pivotal role in actin polymerisation. Validation experiments showed that overexpression and inhibition of miR-181c had no impact on BRK1 mRNA expression but did in fact modulate protein expression, suggesting that miR-181c regulates BRK1 at the translational level. We demonstrated that primary T cell activation resulted in downregulation of miR-181c and upregulation of BRK1 protein expression, further strengthening our hypothesis that the miR-181c-BRK1 axis may play an important role in T cell activation. Next, we found that loss of BRK1 resulted in reduced T cell activation as shown by decreased expression of CD69 and CD154. Furthermore, we showed that downregulation of BRK1 expression by shRNA resulted in reduced actin polymerisation after T cell stimulation. Reduced expression of BRK1 led to a marked reduction in the total area (in square micrometers) of F-actin accumulation at T cell contact sites and synapses with B cells indicating defective immune synapse formation. Moreover, reduced BRK1 expression resulted in defect in lamellipodia formation in response to T cell receptor stimulation. Similarly, ectopic expression of miR-181c in Jurkat T cells also led to a reduction in T cell activation and actin polymerisation coupled with defects in immune synapse and lamellipodia formation, hence confirming the important role of the miR-181c-BRK1 axis in T cell activation. Lastly, we demonstrated that suppression of BRK1 induced reduced expression of other pivotal proteins in the WAVE2 complex including WAVE2, Abi1 and Sra1. This suggests that impairment of actin polymerisation-dependent T cell functions were a result of instability of the WAVE2 complex following BRK1 suppression. Conclusion For the first time, we hereby demonstrate that BRK1 is a target of miR-181c. Moreover, we have highlighted the potential role of the miR-181c-BRK1 axis in impaired actin polymerisation-dependent T cell function and immune synapse formation. Deregulation of the miR-181c-BRK1 axis requires further evaluation in haematological malignancies. Disclosures No relevant conflicts of interest to declare.

IFNγ Licensed Human Bone Marrow Derived Mesenchymal Stromal Cells Inhibit T Cell Cytokine Production by a Mechanism Independent of Indoleamine 2 3-Dioxygenase (IDO) Activity

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1255-1255
Author(s):  
Raghavan Chinnadurai ◽  
Ian Copland ◽  
Seema Patel ◽  
Jacques Galipeau
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Intracellular Cytokine Staining ◽  
Cytokine Secretion ◽  
T Cell Proliferation ◽  
Indoleamine 2 ◽  
T Cell Function ◽  
Inhibitory Potential

Abstract Abstract 1255 Human Bone marrow derived Mesenchymal Stromal Cells (MSCs) inhibit activation-mediated T cell proliferation. This functional interaction serves nearly universally as a surrogate assay for immune suppressive activity and potency of MSCs in vitro. However the role of MSCs in inhibiting T cell function, cytokine production in particular, has not been investigated thoroughly. In the present study we have compared resting MSCs with IFNγ licensed MSCs for their ability to inhibit activated T cell function such as cytokine secretion and degranulation through intracellular cytokine staining assays. PBMCs cocultured with resting or inflammatory cytokine licensed MSCs were stimulated with the super antigen Stephylococcal Enterotoxin B (SEB) for 12–14hours in the presence of Brefeldin A. Intracellular cytokine staining was performed on the T cells to detect the Interferon gamma (IFNγ), Tumor Necrosis Alpha (TNFα) and Interleukin-2 (IL-2). Our results demonstrate that resting MSCs do not inhibit T cell cytokine secreting function. However, IFNγ and IFNγ plus TNFα licensed MSCs dose dependently inhibit IFNγ secretion by T cells. Our results also show that IFNγ and IFNγ plusTNFα licensed MSCs not only inhibit cytokine secretion but also inhibit dregranulation of activated T cells. Boolean gating analysis demonstrates that IFNγ and IFNγ plusTNFα licensed MSCs inhibit triple cytokine producing highly inflammatory IFNγ +TNFα +IL2+T cells. Phenotypic analysis of MSCs demonstrates that IFNγ licensing upregulate indoleamine 2 3-dioxygenase (IDO) and B7-H1. Blocking of IDO activity with 1-Methyl D,L Tryptophan (1MT) will abolish MSC-mediated blockade of T cell proliferation. However, 1MT does not reverse the MSC blockade of T cell cytokine secretion. Phenotypical analysis of T cells demonstrate that PD1+ cells are inhibited while PD1- cells are not inhibited suggesting the role of B7-H1 and PD-1 inhibitory pathway is involved in the inhibitory potential of IFNγ licensed MSCs. Interestingly, the inhibitory potential of IFNγ licensed MSCs has been observed only with the SEB stimulation but not with anti-CD3, CD28 stimulation. This suggests that MHC-TCR interaction is necessary for the inhibitory effect of IFNγ licensed MSCs. Our results demonstrate the superiority of IFNγ licensed MSCs in inhibiting multiple cytokine producing T cell function independent of IDO activity. Our results also provide the rationale for use of IFNγ licensed MSCs in autologous immunosuppressive cell therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ionic Regulation of T-Cell Function and Anti-Tumour Immunity

2021 ◽  
Vol 22 (24) ◽  
pp. 13668
Author(s):  
Pierpaolo Ginefra ◽  
Helen Carrasco Hope ◽  
Mattia Spagna ◽  
Alessandra Zecchillo ◽  
Nicola Vannini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
T Cell Function

The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism.

Sign in / Sign up

Export Citation Format

Share Document