scholarly journals P038 Microbial regulation of T-cell fate towards regulatory profiles during T-cell transfer induced colitis

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S150-S151
Author(s):  
A Machicote ◽  
P Pelczar ◽  
M Nawrocki ◽  
A Fazio ◽  
B Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibiotic Treatment ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Treg Cells ◽  
Effector T Cells ◽  
Cell Transfer ◽  
Cell Plasticity ◽  
T Cell Transfer

Abstract Background During Inflammatory Bowel Diseases (IBD), CD4+ effector T cells are main mediators of the tissue damage. Among them, Th17 cells strongly contribute to the inflammatory response. Interestingly, our lab previously showed that Th17 cells can convert into regulatory T cells, thereby controlling inflammation. However, the forces controlling the plasticity of T cells during IBD remain largely unknown. Our aim is to understand, how CD4+ T-cell plasticity can be modulated from a pro-inflammatory towards an anti-inflammatory profile during IBD. It is currently known that both Th17 and Foxp3 Treg cells can recognize microbiota-derived antigens and that changes in the microbiota are commonly observed in IBD. We hypothesize that the microbiota is a key candidate to modulate T-cell plasticity. Methods T-cell transfer mouse IBD model was performed by transferring CD4+ naïve T-cells into Rag1 -/- receptors. To study Th17 T-cell plasticity, we used as donors IL-17A Fate-mapping mice. These mice comprise of an IL-17ACRE/R26fl/fl YFP construct where the cells that previously expressed IL-17A turn into YFP+ cells. Ciprofloxacin and metronidazole, two antibiotics commonly given to IBD patients, were used to treat the mice. Stool microbiota composition was analysed longitudinally by 16S rRNA amplicon sequencing. Colitis development was evaluated by colonoscopy. CD4+ T cells were isolated from the colon and reporter expression was analysed by Flow Cytometry. Results After T-cell transfer colitis induction, ciprofloxacin and metronidazole treatment alleviated gut inflammation, as determined by weight loss (p=0.005), colitis score (p=0.004) and colon length (p=0.01). Antibiotic treatment increased the relative abundance of bacteria previously associated with beneficial IBD outcomes (e.g. Bifidobacterium). Interestingly, colonic CD4+ T-cells showed an increased conversion from Th17 towards a Foxp3+ Treg profile (Foxp3ExTh17) (p=0.03). Conclusion The conversion of CD4+ effector T cells into Treg cells is a promising approach to counteract inflammation in IBD patients. We showed that antibiotic treatment not only correlates with a relative expansion of beneficial bacteria, but perhaps most interesting, with an increased conversion of effector Th17 cells towards Foxp3+ Treg cells in the colon. Altogether, these data support the manipulation of the microbiota as a tool to revert intestinal inflammation in IBD patients.

scholarly journals Graded RhoA GTPase Expression in Treg Cells Distinguishes Tumor Immunity From Autoimmunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Khalid W. Kalim ◽  
Jun-Qi Yang ◽  
Vishnu Modur ◽  
Phuong Nguyen ◽  
Yuan Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Tumor Immunity ◽  
Th17 Cell ◽  
Treg Cells ◽  
Effector T Cells ◽  
Conditional Knockout ◽  
Cell Plasticity ◽  
Cell Homeostasis

RhoA of the Rho GTPase family is prenylated at its C-terminus. Prenylation of RhoA has been shown to control T helper 17 (Th17) cell-mediated colitis. By characterizing T cell-specific RhoA conditional knockout mice, we have recently shown that RhoA is required for Th2 and Th17 cell differentiation and Th2/Th17 cell-mediated allergic airway inflammation. It remains unclear whether RhoA plays a cell-intrinsic role in regulatory T (Treg) cells that suppress effector T cells such as Th2/Th17 cells to maintain immune tolerance and to promote tumor immune evasion. Here we have generated Treg cell-specific RhoA-deficient mice. We found that homozygous RhoA deletion in Treg cells led to early, fatal systemic inflammatory disorders. The autoimmune responses came from an increase in activated CD4+ and CD8+ T cells and in effector T cells including Th17, Th1 and Th2 cells. The immune activation was due to impaired Treg cell homeostasis and increased Treg cell plasticity. Interestingly, heterozygous RhoA deletion in Treg cells did not affect Treg cell homeostasis nor cause systemic autoimmunity but induced Treg cell plasticity and an increase in effector T cells. Importantly, heterozygous RhoA deletion significantly inhibited tumor growth, which was associated with tumor-infiltrating Treg cell plasticity and increased tumor-infiltrating effector T cells. Collectively, our findings suggest that graded RhoA expression in Treg cells distinguishes tumor immunity from autoimmunity and that rational targeting of RhoA in Treg cells may trigger anti-tumor T cell immunity without causing autoimmune responses.

Abstract 2310: With a little help from CD4 T cells in adoptive T-cell transfer

2016 ◽  
Author(s):  
Else M. Inderberg ◽  
Sébastien Wälchli ◽  
Marit R. Myhre ◽  
Kari Lislerud ◽  
Gunnar Kvalheim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
T Cell Transfer

scholarly journals Tumor Progression Locus 2 Differentially Regulates IFNγ and IL-17 Production by Effector CD4+ T Cells in a T Cell Transfer Model of Colitis

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0119885 ◽  
Author(s):  
Nicole V. Acuff ◽  
Xin Li ◽  
Rebecca Kirkland ◽  
Tamas Nagy ◽  
Wendy T. Watford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Progression ◽  
Cd4 T Cells ◽  
Transfer Model ◽  
Cell Transfer ◽  
T Cell Transfer

scholarly journals Enhanced Inflammatory Potential of CD4+ T-Cells That Lack Proteasome Immunosubunit Expression, in a T-Cell Transfer-Based Colitis Model

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e95378 ◽  
Author(s):  
Orhan Rasid ◽  
Chantal Meulenbroeks ◽  
Andrea Gröne ◽  
Dietmar Zaiss ◽  
Alice Sijts
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Transfer ◽  
T Cell Transfer ◽  
Colitis Model

scholarly journals Cell membrane-anchored and tumor-targeted IL-12 (attIL12)-T cell therapy for eliminating large and heterogeneous solid tumors

2022 ◽  
Vol 10 (1) ◽  
pp. e003633
Author(s):  
Jiemiao Hu ◽  
Qing Yang ◽  
Wendong Zhang ◽  
Hongwei Du ◽  
Yuhui Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Membrane ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Cell Transfer ◽  
T Cell Therapy ◽  
A Cell ◽  
T Cell Transfer ◽  
Heterogeneous Solid

BackgroundAdoptive T-cell transfer has become an attractive therapeutic approach for hematological malignancies but shows poor activity against large and heterogeneous solid tumors. Interleukin-12 (IL-12) exhibits potent antitumor efficacy against solid tumors, but its clinical application has been stalled because of toxicity. Here, we aimed to develop a safe approach to IL-12 T-cell therapy for eliminating large solid tumors.MethodsWe generated a cell membrane-anchored IL-12 (aIL12), a tumor-targeted IL-12 (ttIL12), and a cell membrane-anchored and ttIL-12 (attIL12) and a cell membrane-anchored and tumor-targeted ttIL-12 (attIL12) armed T cells, chimeric antigen receptor-T cells, and T cell receptor-T (TCR-T) cells with each. We compared the safety and efficacy of these armed T cells in treating osteosarcoma patient-derived xenograft tumors and mouse melanoma tumors after intravenous infusions of the armed T cells.ResultsattIL12-T cell infusion showed remarkable antitumor efficacy in human and mouse large solid tumor models. Mechanistically, attIL12-T cells targeted tumor cells expressing cell-surface vimentin, enriching effector T cell and interferon γ production in tumors, which in turn stimulates dendritic cell maturation for activating secondary T-cell responses and tumor antigen spreading. Both attIL12- and aIL12-T-cell transfer eliminated peripheral cytokine release and the associated toxic effects.ConclusionsThis novel approach sheds light on the safe application of IL-12-based T-cell therapy for large and heterogeneous solid tumors.

scholarly journals Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation

2005 ◽  
Vol 202 (5) ◽  
pp. 697-706 ◽  
Author(s):  
Dawn M. Jelley-Gibbs ◽  
Deborah M. Brown ◽  
John P. Dibble ◽  
Laura Haynes ◽  
Sheri M. Eaton ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
High Efficiency ◽  
Influenza Infection ◽  
Cd4 T Cell ◽  
Intermediate Phenotypes ◽  
Donor T Cells ◽  
T Cell Transfer ◽  
Kinetics Of

The kinetics of presentation of influenza virus–derived antigens (Ags), resulting in CD4 T cell effector and memory generation, remains undefined. Naive influenza-specific CD4 T cells were transferred into mice at various times after influenza infection to determine the duration and impact of virus-derived Ag presentation. Ag-specific T cell responses were generated even when the donor T cells were transferred 3–4 wk after viral clearance. Transfer of naive CD4 T cells during early phases of infection resulted in a robust expansion of highly differentiated effectors, which then contracted to a small number of memory T cells. Importantly, T cell transfer during later phases of infection resulted in a modest expansion of effectors with intermediate phenotypes, which were capable of persisting as memory with high efficiency. Thus, distinct stages of pathogen-derived Ag presentation may provide a mechanism by which T cell heterogeneity is generated and diverse memory subsets are maintained.

Adoptive Transfer of Adenovirus Specific T-Cells in Children with Systemic Adenovirus Infection after Allogeneic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 80-80
Author(s):  
Tobias F. Feuchtinger ◽  
Susanne Matthes-Martin ◽  
Celine Richard ◽  
Thomas Lion ◽  
Klaus Hamprecht ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Adoptive Transfer ◽  
Cell Transfer ◽  
New Treatment ◽  
T Cell Transfer

Abstract Allogeneic stem cell transplantation (SCT) has become an increasing treatment option for a variety of malignant and non-malignant disease. During immune reconstitution the host is at significant risk for viral infections. Human adenovirus (HAdV) infection is especially in children an important and serious complication. Virus-specific T-cells are essential for the clearance of HAdV, since antiviral chemotherapy has been insufficient to date. We present a new treatment option using virus-specific donor T-cells for adoptive transfer of immunity to patients with systemic HAdV-infection. We isolated in 6 patients with systemic HAdV-infection after SCT virus-specific T-cells of the donor, according to INF-γ secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4+ and CD8+ T-cells. Between 5-50x103/kg T-cells were infused for adoptive transfer. For follow-up, the infection and the in-vivo expansion of infused T-cells were evaluated. Isolated cells showed high specificity and markedly reduced but residual alloreactivity in-vitro. In three of four evaluable patients the infused T-cells underwent an in-vivo expansion and in these three patients the viral load decreased in peripheral blood after adoptive T-cell transfer. In-vivo expansion of specific T-cells was dose-independent. T-cell infusion was well tolerated. One patient experienced GvHD°II of the skin after T-cell transfer. In conclusion specific T-cell immunotherapy as a new treatment approach for children was performed in 6 cases of systemic HAdV-infection after allogeneic SCT. Induction of a specific T-cell response through adoptive transfer has been shown feasible and effective to protect from HAdV-related complications.

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