Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

2018 ◽  
Author(s):  
Hachemi Kadri ◽  
Taher E. Taher ◽  
Qin Xu ◽  
Richard T. Bryan ◽  
Benjamin E. Willcox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Serum Stability ◽  
T Cell Immune Responses ◽  
Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

2018 ◽  
Author(s):  
Hachemi Kadri ◽  
Taher E. Taher ◽  
Qin Xu ◽  
Richard T. Bryan ◽  
Benjamin E. Willcox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Serum Stability ◽  
T Cell Immune Responses ◽  
Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

scholarly journals Eomes Impedes Durable Response to Tumor Immunotherapy by Inhibiting Stemness, Tissue Residency, and Promoting the Dysfunctional State of Intratumoral CD8+ T Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Runzi Sun ◽  
Yixian Wu ◽  
Huijun Zhou ◽  
Yanshi Wu ◽  
Zhongzhou Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Critical Role ◽  
Cell Subset ◽  
Tumor Immunotherapy ◽  
Genetic Circuit ◽  
Durable Response ◽  
T Cell Immune Responses ◽  
Deficient Mice

Sustaining efficacious T cell-mediated antitumor immune responses in the tumor tissues is the key to the success of cancer immunotherapy. Current strategies leverage altering the signals T cells sense in the tumor microenvironment (TME). Checkpoint inhibitor-based approaches block inhibitory signals such as PD-1 whereas cytokine-based therapies increase the level of immune-stimulatory cytokines such as IL-2. Besides extrinsic signals, the genetic circuit within T cells also participates in determining the nature and trajectory of antitumor immune responses. Here, we showed that efficacy of the IL33-based tumor immunotherapy was greatly enhanced in mice with T cell-specific Eomes deficiency. Mechanistically, we demonstrated that Eomes deficient mice had diminished proportions of exhausted/dysfunctional CD8+ T cells but increased percentages of tissue resident and stem-like CD8+ T cells in the TME. In addition, the IFNγ+TCF1+ CD8+ T cell subset was markedly increased in the Eomes deficient mice. We further demonstrated that Eomes bound directly to the transcription regulatory regions of exhaustion and tissue residency genes. In contrast to its role in inhibiting T cell immune responses at the tumor site, Eomes promoted generation of central memory T cells in the peripheral lymphoid system and memory recall responses against tumor growth at a distal tissue site. Finally, we showed that Eomes deficiency in T cells also resulted in increased efficacy of PD-1-blockade tumor immunotherapy. In all, our study indicates that Eomes plays a critical role in restricting prolonged T cell-mediated antitumor immune responses in the TME whereas promoting adaptive immunity in peripheral lymphoid organs.

Su.67. Monocytes Modulate T-Cell Immune Responses in a Pge2-Cox-2 Dependent Manner and Induce Foxp3+-Cd4+- T-Cells

2006 ◽  
Vol 119 ◽  
pp. S183
Author(s):  
Sheraz Yaqub ◽  
Tone Bryn ◽  
Milada Mahic ◽  
Einar Aandahl ◽  
Kjetil Tasken
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Dependent Manner ◽  
T Cell Immune Responses ◽  
Cox 2

scholarly journals LPS-activated monocytes suppress T-cell immune responses and induce FOXP3+ T cells through a COX-2-PGE2-dependent mechanism

2007 ◽  
Vol 20 (2) ◽  
pp. 235-245 ◽  
Author(s):  
T. Bryn ◽  
S. Yaqub ◽  
M. Mahic ◽  
K. Henjum ◽  
E. M. Aandahl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Immune Responses ◽  
Cox 2 ◽  
Activated Monocytes ◽  
Dependent Mechanism

scholarly journals Role of IL-2 secreted by PADRE-specific CD4+ T cells in enhancing E7-specific CD8+ T-cell immune responses

Gene Therapy ◽  
2008 ◽  
Vol 15 (9) ◽  
pp. 677-687 ◽  
Author(s):  
D Kim ◽  
A Monie ◽  
L He ◽  
Y-C Tsai ◽  
C-F Hung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
T Cell Immune Responses

scholarly journals NF90 regulates inducible IL-2 gene expression in T cells

2007 ◽  
Vol 204 (5) ◽  
pp. 971-977 ◽  
Author(s):  
Lingfang Shi ◽  
Wayne R. Godfrey ◽  
Joseph Lin ◽  
Guohua Zhao ◽  
Peter N. Kao
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Rna Binding ◽  
Proximal Promoter ◽  
Target Sequence ◽  
Chimeric Mice ◽  
Mrna Stabilization ◽  
T Cell Immune Responses

Activation of T cells induces the production of T cell growth and survival factor interleukin (IL) 2. Regulatory T cells intrinsically fail to induce IL-2 expression upon activation and can suppress IL-2 production in conventional T cells. Thus, the control of IL-2 expression is critically important to T cell immune responses, yet the mechanisms remain incompletely understood. Nuclear factor (NF) 90 is a zinc-finger DNA- and double-stranded RNA-binding protein subunit that binds specifically to the antigen receptor response element (ARRE)/NF of activated T cells target sequence in the IL-2 proximal promoter. Inducible binding of NF90 to the IL-2 promoter in vivo is shown by chromatin immunoprecipitation. NF90 gene-targeted mice exhibit perinatal lethality. Compared with newborn NF90+/+ mice, newborn NF90−/− mice demonstrate severe impairment of IL-2 expression. Compared with wild-type cells, T cells deficient in NF90 are impaired in ARRE and IL-2 transcriptional activation and IL-2 mRNA stabilization. Fetal liver cells from NF90 gene-targeted mice were transplanted into irradiated adult recombination activating gene (RAG)–2−/− and IL-2Rγ−/− mice deficient in T cells, B cells, and natural killer cells. NF90+/+- and NF90−/−-RAG chimeric mice showed grossly normal repopulation of the thymus and spleen, but only NF90−/− T cells were severely impaired in IL-2 gene expression. Compared with littermates, NF90−/− RAG chimeric mice exhibited profound T cell lymphocytopenia in the peripheral circulation. Thus, NF90 regulates inducible IL-2 transcription, mRNA stability, and gene expression in T cells and represents a novel therapeutic target for the modulation of T cell immune responses.

scholarly journals Erratum: Role of IL-2 secreted by PADRE-specific CD4+ T cells in enhancing E7-specific CD8+ T-cell immune responses

Gene Therapy ◽  
2008 ◽  
Vol 15 (9) ◽  
pp. 702-702
Author(s):  
D Kim ◽  
A Monie ◽  
L He ◽  
Y-C Tsai ◽  
C-F Hung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
T Cell Immune Responses

scholarly journals Mice Lacking Expression of the Chemokines Ccl21-Ser and Ccl19 (plt Mice) Demonstrate Delayed but Enhanced T Cell Immune Responses

2001 ◽  
Vol 193 (2) ◽  
pp. 207-218 ◽  
Author(s):  
Shigeyuki Mori ◽  
Hideki Nakano ◽  
Kentaro Aritomi ◽  
Chrong-Reen Wang ◽  
Michael D. Gunn ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Response ◽  
T Cell Response ◽  
Lymphoid Organs ◽  
Cell Responses ◽  
T Cell Immune Responses ◽  
Secondary Lymphoid Organs

The paucity of lymph node T cells (plt) mutation leads to a loss of CCL21 and CCL19 expression in secondary lymphoid organs. plt mice have defects in the migration of naive T cells and activated dendritic cells into the T cell zones of lymphoid organs, suggesting that they would have defects in T cell immune responses. We now demonstrate T cell responses in plt mice are delayed but ultimately enhanced. Responses to contact sensitization are decreased at day 2 after priming but increased at day 6. After subcutaneous immunization, antigen-specific T cell proliferation and cytokine production in plt mice are increased and remain markedly elevated for at least 8 wk. Compared with wild-type mice, a proportion of T cell response in plt mice are shifted to the spleen, and prior splenectomy reduces the T cell response in draining lymph nodes. After immunization of plt mice, T cells and dendritic cells colocalize in the superficial cortex of lymph nodes and in splenic bridging channels, but not in T cell zones. These results demonstrate that plt mice mount robust T cell responses despite the failure of naive T cells and activated dendritic cells to enter the thymus dependent areas of secondary lymphoid organs.

scholarly journals CD25+CD4+ Regulatory T Cells from the Peripheral Blood of Asymptomatic HIV-infected Individuals Regulate CD4+ and CD8+ HIV-specific T Cell Immune Responses In Vitro and Are Associated with Favorable Clinical Markers of Disease Status

2004 ◽  
Vol 200 (3) ◽  
pp. 331-343 ◽  
Author(s):  
Audrey L. Kinter ◽  
Margaret Hennessey ◽  
Alicia Bell ◽  
Sarah Kern ◽  
Yin Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Cellular Proliferation ◽  
Cell Contact ◽  
Hiv Disease ◽  
T Cell Immune Responses

Human immunodeficiency virus (HIV) disease is associated with loss of CD4+ T cells, chronic immune activation, and progressive immune dysfunction. HIV-specific responses, particularly those of CD4+ T cells, become impaired early after infection, before the loss of responses directed against other antigens; the basis for this diminution has not been elucidated fully. The potential role of CD25+CD4+ regulatory T cells (T reg cells), previously shown to inhibit immune responses directed against numerous pathogens, as suppressors of HIV-specific T cell responses was investigated. In the majority of healthy HIV-infected individuals, CD25+CD4+ T cells significantly suppressed cellular proliferation and cytokine production by CD4+ and CD8+ T cells in response to HIV antigens/peptides in vitro; these effects were cell contact dependent and IL-10 and TGF-β independent. Individuals with strong HIV-specific CD25+ T reg cell function in vitro had significantly lower levels of plasma viremia and higher CD4+: CD8+ T cell ratios than did those individuals in whom this activity could not be detected. These in vitro data suggest that CD25+CD4+ T reg cells may contribute to the diminution of HIV-specific T cell immune responses in vivo in the early stages of HIV disease.

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