Disease relevance of T11TS-induced T-cell signal transduction through the CD2-mediated calcineurin–NFAT pathway: Perspectives in glioma immunotherapy

Chaudhuri, Suhnrita; Bhattacharya, Debanjan; Singh, Manoj Kumar; Moitra, Saibal; Ronsard, Larance; Ghosh, Tushar K.; Chaudhuri, Swapna

doi:10.1016/j.molimm.2015.06.002

Cited by 11 publications

(22 citation statements)

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“…The T11TS‐induced enhancement of PI3K expression and AKT expression and activation observed herein seem to be mediated by augmented CD28 and CD80 expressions and CTLA‐4 downregulation on T11TS therapy (Chaudhuri et al, ). In parallel studies we have noted that p59fyn levels do not rise appreciably immediately after the application of the first (ET1) dose of T11TS but rise significantly with the second (ET2) and third (ET3) doses of T11TS administration (Chaudhuri et al, ). It has been shown that PI3K activity is influenced by p59fyn (Prasad et al, ).…”

Section: Discussionmentioning

confidence: 91%

“…It has further been shown in prior papers that T11TS favors T‐cell survival in glioma conditions by apoptotic inhibition of T‐cells through both the intrinsic and extrinsic apoptotic pathways (Bhattacharjee et al, ). Further work from our lab has shown that T11TS immunotherapy of glioma‐bearing rats causes activation of the T‐cell CD2‐mediated NFAT‐calcineurin pathway which is concerned with T‐cell survival and proliferation (Chaudhuri et al, ). The role of the PI3K‐AKT pathway in inhibition of apoptosis and promotion of cell survival is well documented (Chang et al, ; Franke, Hornik, Segev, Shostak, & Sugimoto, ).…”

Section: Introductionmentioning

confidence: 99%

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T11TS immunotherapy repairs PI3K‐AKT signaling in T‐cells: Clues toward enhanced T‐cell survival in rat glioma model

Chaudhuri¹,

Singh²,

Bhattacharya³

et al. 2017

Journal Cellular Physiology

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Malignant glioma is the most fatal of astrocytic lineage tumors despite therapeutic advances. Onset and progression of gliomas is accompanied by severe debilitation of T-cell defense and T-cell survival. One of the chief contributors to T-cell survival downstream of activation is the PI3K-AKT pathway. Our prior studies showed that the novel immunotherapeutic molecule T11-target structure (T11TS) blocks T-cell apoptosis in glioma. We also showed activation of immunological synapse components and calcineurin-NFAT pathway following T11TS immunotherapy of glioma-bearing rats. This lead to investigations whether such T-cell activation upon T11TS therapy translates into activation of downstream PI3K/AKT signals which may be related to observed blockade of T-cell apoptosis. For the purpose, we assessed by flowcytometry and immunoblotting, expressions of PI3K, PDK1, AKT, p-AKT, and PTEN in splenic T-cells of normal, experimentally-induced glioma-bearing rats and glioma-bearing rats receiving first, second and third doses of T11TS. We also determined comparative nuclear translocation of NF-κB across groups. We found significant increases in T-cell expressions of PDK1, PI3K, and p-AKT in T11TS-treated animal groups compared to sharp downregulations in glioma. AKT levels remained unchanged across groups. PTEN levels declined sharply after T11TS immunotherapy. T11TS also caused enhanced NF-κB translocation to the T-cell nucleus compared to glioma group. Results showed heightened activation of the PI3K-AKT pathway in glioma-bearing rats following T11TS immunotherapy. These results illustrate the novel role of T11TS immunotherapy in ameliorating the PI3K pathway in T-cells in glioma-bearing animals to enhance T-cell survival, according greater defense against glioma. The study thus has far-reaching clinical outcomes.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

T11TS immunotherapy repairs PI3K‐AKT signaling in T‐cells: Clues toward enhanced T‐cell survival in rat glioma model

Chaudhuri¹,

Singh²,

Bhattacharya³

et al. 2017

Journal Cellular Physiology

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“…The CD2 expressions of microglia were boosted with three doses of T11TS administration, in comparison with the diseased state. CD2‐ligand binding triggers the signals for T cell activation and opens up the alternative signalling pathway . The CD2‐T11TS interaction activates the resting microglia, the resident macrophages of brain with upregulation of several activation markers like CD11b, CD25, CD45 and CD4 .…”

Section: Discussionmentioning

confidence: 99%

“…T11TS, a novel immunomodulator with documented immunostimulatory and non‐toxic efficacy, has been isolated from SRBC membrane and characterized in our laboratory and have demonstrated potent antineoplastic action against glioma . T11TS acts as a ligand of CD2 receptors on several immunocytes .…”

Section: Introductionmentioning

confidence: 99%

T11TS immunotherapy augments microglial and lymphocyte protective immune responses against Cryptococcus neoformans in the brain

Hazra¹,

Sk²,

Datta³

et al. 2018

Scand J Immunol

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Cryptococcus neoformans, the encapsulated yeast acquired through inhalation, remains localized in lungs, but harbours the CNS in immunocompromised individuals. Several treatment regimes have failed combating this disease totally, but long‐term usage of drugs leads to organ damage. As T11‐target structure (T11TS) has documented profound immune potentiation, we aimed to investigate the role of microglia, pivotal immune cells of brain in ameliorating cryptococcosis, with T11TS immunotherapy. Murine model with C neoformans infection was prepared by intraperitoneal injection and the brains of rats examined 7 days post‐infections for histopathology by PAS and Alcian blue staining corroborated with organ fungal burden evidencing restorative T11TS action on Cryptococcal meningitis. Immunotherapy with three doses of T11TS, a CD2 ligand, in C neoformans infected rats, upregulates toll‐like receptors 2, −4 and −9 of microglia, indicating increased phagocytosis of the fungus. Flowcytometric analysis revealed increased numbers of T11TS treated brain infiltrating CD4+ and CD8+ T‐lymphocytes along with increased MHC I and MHC II on microglia, activating the infiltrating lymphocytes aiding the killing mechanism. Present study also indicated that T11TS increased production of Th1 inflammatory cytokines conducive to fungal elimination while the inhibitory Th2 cytokines were dampened. This preclinical study is first of its kind to show that T11TS effected profound immune stimulation of microglial activity of C neoformans infected rats eradicating residual fungal burden from the brain and can be a useful therapeutic strategy in fighting against this deadly disease.

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“…The amount of protein was estimated by BCA Assay (Pierce). Tat proteins were run on 12% SDS-PAGE and transferred to the nitrocellulose membrane (BIORAD) using standard methods (Chaudhuri et al, 2015; Mohankumar et al, 2015; Sridharan et al, 2015). The membrane was incubated with anti-myc antibody followed by Anti-rabbit IgG conjugated to HRP.…”

Section: Methodsmentioning

confidence: 99%

Impact of Genetic Variations in HIV-1 Tat on LTR-Mediated Transcription via TAR RNA Interaction

et al. 2017

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HIV-1 evades host defense through mutations and recombination events, generating numerous variants in an infected patient. These variants with an undiminished virulence can multiply rapidly in order to progress to AIDS. One of the targets to intervene in HIV-1 replication is the trans-activator of transcription (Tat), a major regulatory protein that transactivates the long terminal repeat promoter through its interaction with trans-activation response (TAR) RNA. In this study, HIV-1 infected patients (n = 120) from North India revealed Ser46Phe (20%) and Ser61Arg (2%) mutations in the Tat variants with a strong interaction toward TAR leading to enhanced transactivation activities. Molecular dynamics simulation data verified that the variants with this mutation had a higher binding affinity for TAR than both the wild-type Tat and other variants that lacked Ser46Phe and Ser61Arg. Other mutations in Tat conferred varying affinities for TAR interaction leading to differential transactivation abilities. This is the first report from North India with a clinical validation of CD4 counts to demonstrate the influence of Tat genetic variations affecting the stability of Tat and its interaction with TAR. This study highlights the co-evolution pattern of Tat and predominant nucleotides for Tat activity, facilitating the identification of genetic determinants for the attenuation of viral gene expression.

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Disease relevance of T11TS-induced T-cell signal transduction through the CD2-mediated calcineurin–NFAT pathway: Perspectives in glioma immunotherapy

Cited by 11 publications

References 50 publications

T11TS immunotherapy repairs PI3K‐AKT signaling in T‐cells: Clues toward enhanced T‐cell survival in rat glioma model

T11TS immunotherapy repairs PI3K‐AKT signaling in T‐cells: Clues toward enhanced T‐cell survival in rat glioma model

T11TS immunotherapy augments microglial and lymphocyte protective immune responses against Cryptococcus neoformans in the brain

Impact of Genetic Variations in HIV-1 Tat on LTR-Mediated Transcription via TAR RNA Interaction

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