NK Cell Adoptive Transfer Combined with Ontak-Mediated Regulatory T Cell Elimination Induces Effective Adaptive Antitumor Immune Responses

Abstract As regulatory T cell (Treg) adoptive therapy continues to develop clinically, there is a need to determine which immunomodulatory agents pair most compatibly with Tregs to enable persistence and stabilize suppressor function. Prior work has shown that mechanistic target of rapamycin inhibition can increase the stability of thymic Tregs. In this study, we investigated the transcriptomic signatures of ex vivo–expanded Tregs after adoptive transfer in the setting of clinically relevant immunosuppression using a nonhuman primate (NHP) model as a prelude to future transplant studies. Here, we found that adding interleukin-2 (IL-2) to rapamycin in vivo supported a logarithmic increase in the half-life of adoptively transferred carboxyfluorescein diacetate succinimidyl ester–labeled, autologous NHP Tregs, effectively doubling the number of cells in the peripheral blood Treg compartment compared with Treg infusion when rapamycin was given alone. Using single-cell transcriptomics, we found that transferred ex vivo–expanded Tregs initially exhibit a gene expression signature consistent with an activated state. Moreover, those cells with the highest levels of activation also expressed genes associated with p53-mediated apoptosis. In contrast, transferred Tregs interrogated at day +20 posttransfer demonstrated a gene signature more similar to published profiles of resting Tregs. Together, these preclinical data further support combining IL-2 and rapamycin in vivo as adjunctive therapy for ex vivo–expanded adoptively transferred Tregs and suggest that the activation status of ex vivo–expanded Tregs is critical to their persistence.

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Enhanced immune responses to an adenovirus CEA vaccine in CD4+CD25+regulatory T-cell inactivated mice

Expert Review of Vaccines ◽

10.1586/14760584.6.1.21 ◽

2007 ◽

Vol 6 (1) ◽

pp. 21-23 ◽

Cited By ~ 1

Author(s):

Geoffrey A Pietersz

Keyword(s):

T Cell ◽

Immune Responses ◽

Regulatory T Cell

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Regulatory T cell adjustment of quorum growth thresholds and the control of local immune responses

Journal of Theoretical Biology ◽

10.1016/j.jtbi.2005.11.010 ◽

2006 ◽

Vol 241 (1) ◽

pp. 134-141 ◽

Cited By ~ 42

Author(s):

N.J. Burroughs ◽

Bruno Miguel Paz Mendes de Oliveira ◽

Alberto Adrego Pinto

Keyword(s):

T Cell ◽

Immune Responses ◽

Regulatory T Cell

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Regulatory T-cell: Regulator of Host Defense in Infection

Journal of Molecular Biology Research ◽

10.5539/jmbr.v7n1p9 ◽

2017 ◽

Vol 7 (1) ◽

pp. 9 ◽

Cited By ~ 2

Author(s):

Mousa Mohammadnia-Afrouzi ◽

Mehdi Shahbazi ◽

Sedigheh Baleghi Damavandi ◽

Ghasem Faghanzadeh Ganji ◽

Soheil Ebrahimpour

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Immune Responses ◽

Regulatory T Cell ◽

Critical Role ◽

The Body ◽

Cell Contact ◽

Infectious Agents ◽

Activated T Cells

Based on diverse activities and production of several cytokines, T lymphocytes and T helper cells are divided into Th1, Th2, Th17 and regulatory T-cell (T regs) subsets based on diverse activities and production of several cytokines. Infectious agents can escape from host by modulation of immune responses as effector T-cells and Tregs. Thus, regulatory T-cells play a critical role in suppression of immune responses to infectious agents such as viruses, bacteria, parasites and fungi and as well as preserving immune homeostasis. However, regulatory T-cell responses can advantageous for the body by minimizing the tissue-damaging effects. The following subsets of regulatory T-cells have been recognized: natural regulatory Tcells, Th3, Tr1, CD8+ Treg, natural killer like Treg (NKTreg) cells. Among various markers of Treg cells, Forkhead family transcription factor (FOXP3) as an intracellular protein is used for discrimination between activated T reg cells and activated T-cells. FOXP3 has a central role in production, thymocyte differentiation and function of regulatory Tcells. Several mechanisms have been indicated in regulation of T reg cells. As, the suppression of T-cells via regulatory T-cells is either mediated by Cell-cell contact and Immunosuppressive cytokines (TGF-Beta, IL-10) mediated.

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Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-γ-producing NK cell and regulatory T cell subsets

Immunobiology ◽

10.1016/j.imbio.2011.07.006 ◽

2011 ◽

Vol 216 (12) ◽

pp. 1256-1263 ◽

Cited By ~ 35

Author(s):

Octavio Aravena ◽

Bárbara Pesce ◽

Lilian Soto ◽

Natalia Orrego ◽

Francisca Sabugo ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

Regulatory T Cell ◽

Th17 Cell ◽

Nk Cell ◽

T Cell Subsets ◽

Cell Populations ◽

Ifn Γ

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Effects of T cell adoptive transfer into nude mice on alveolar bone resorption induced by endotoxin

Journal of Periodontal Research ◽

10.1111/j.1600-0765.1996.tb00510.x ◽

1996 ◽

Vol 31 (6) ◽

pp. 414-422 ◽

Cited By ~ 37

Author(s):

Takashi Ukai ◽

Yoshitaka Hara ◽

Lhachi Kato

Keyword(s):

T Cell ◽

Bone Resorption ◽

Nude Mice ◽

Adoptive Transfer ◽

Alveolar Bone ◽

Cell Adoptive Transfer

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Baculovirus activates murine dendritic cells and induces non-specific NK cell and T cell immune responses

Cellular Immunology ◽

10.1016/j.cellimm.2009.12.005 ◽

2010 ◽

Vol 262 (1) ◽

pp. 35-43 ◽

Cited By ~ 37

Author(s):

Tomoyuki Suzuki ◽

Myint Oo Chang ◽

Masayuki Kitajima ◽

Hiroshi Takaku

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Nk Cell ◽

T Cell Immune Responses

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Lack of Effect of Murine Norovirus Infection on the CD4+ CD45RBhigh T-cell Adoptive Transfer Mouse Model of Inflammatory Bowel Disease

Comparative Medicine ◽

10.30802/aalas-cm-19-000009 ◽

2020 ◽

Vol 70 (1) ◽

pp. 16-24

Author(s):

Charlie C Hsu ◽

Karuna Patil ◽

Audrey Seamons ◽

Thea L Brabb ◽

Piper M Treuting ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

T Cell ◽

Mouse Model ◽

Adoptive Transfer ◽

Bowel Disease ◽

Murine Norovirus ◽

Laboratory Mice ◽

Inflammatory Bowel ◽

Cell Adoptive Transfer

Murine norovirus (MNV) infection is highly prevalent in laboratory mice. Although MNV infection does not typically induce clinical disease in most laboratory mice, infection may nonetheless affect mouse models of disease by altering immune responses. We previously reported that MNV altered the bacterial-induced mouse model of inflammatory bowel disease (IBD) using Helicobacter-infected Mdr1a–/– mice. Therefore, we hypothesized that MNV infection would exacerbate another mouse model of IBD, the T-cell adoptive transfer (AT) model. In this model, Helicobacter infection is used to accelerate the progression of IBD induced by AT of naïve CD4+CD45RBhigh T cells into B6.129S7- Rag1tm1Mom/J (Rag1–/–) mice. We evaluated the effects of MNV infection in both Helicobacter-accelerated as well as Helicobacter-free AT models. In our studies, Helicobacter-infected Rag1–/– mice that received CD4+CD45RBhigh T cells through AT rapidly developed weight loss and typhlocolitis; MNV infection had no effect on disease severity or rate of progression. In the absence of Helicobacter infection, progression of IBD caused by AT of CD4+CD45RBhigh T cells was slower and typhlocolitis was less severe; this inflammation likewise was unaltered by MNV infection. These results indicate that MNV infection does not alter IBD progression and severity in the CD4+CD45RBhigh T-cell AT model in Rag1–/– mice.

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