Alloactivation of Naïve CD4+CD8−CD25+T Regulatory Cells: Expression of CD8α Identifies Potent Suppressor Cells That Can Promote Transplant Tolerance Induction

Verma, Nirupama D.; Robinson, Catherine M.; Carter, Nicole; Wilcox, Paul; Tran, Giang; Wang, Chaunmin; Sharland, Alexandra; Nomura, Masaru; Plain, Karren M.; Bishop, Gail; Hodgkinson, Suzanne; Hall, Bruce M.

doi:10.3389/fimmu.2019.02397

Cited by 10 publications

(11 citation statements)

References 57 publications

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“…Expansion with anti-CD3 and anti-CD28-coated beads and IL-2 resulted in 152.8 ± 17.1-fold expansion (Figure 2A, n = 21), with largely retained Foxp3 expression (63.5± 8.3% FoxP3 + , Figure E1B) and CD25 expression (93.6 ± 1.5% CD25 + ) at day 7. They also upregulated CD8 (81.3 ± 2.4% CD8 + ) at day 7, as reported previously (14). The expanded cells dose-dependently suppressed in vitro proliferation of polyclonally stimulated CD4 + CD25 low Tconv (Figure 2B).…”

Section: Resultssupporting

confidence: 89%

Ex vivodelivery of regulatory T cells for control of alloimmune priming in the donor lung

Miyamoto

Takahagi

Ohsumi

et al. 2021

Preprint

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Rationale: Survival after lung transplantation (LTx) is hampered by uncontrolled inflammation and alloimmunity. Regulatory T cells (Tregs) are being studied for post-implantation cell therapy in solid organ transplantation. Whether these systemically administered Tregs can function at the appropriate location and time is an important concern. Objectives: We hypothesized that in vitro expanded, recipient-derived Tregs can be delivered to donor lungs prior to LTx via ex vivo lung perfusion (EVLP), maintaining their immunomodulatory ability. Methods: In a rat model, Wistar Kyoto (WKy) CD4+CD25high Tregs were expanded in vitro prior to EVLP. Expanded Tregs were administered to Fisher 344 (F344) donor lungs during EVLP; left lungs were transplanted into WKy recipients. Treg localization and function post-transplant were assessed. In a proof-of-concept experiment, cryopreserved expanded human CD4+CD25+CD127low Tregs were thawed and injected into discarded human lungs during EVLP. Measurements and Main Results: Rat Tregs entered the lung parenchyma and retained suppressive function. Expanded Tregs had no adverse effect on donor lung physiology during EVLP; lung water as measured by wet-to-dry weight ratio was reduced by Treg therapy. The administered cells remained in the graft at 3 days post-transplant where they reduced activation of intragraft effector CD4+ T cells; these effects were diminished by day 7. Human Tregs entered the lung parenchyma during EVLP where they expressed key immunoregulatory molecules (CTLA4+, 4-1BB+, CD39+, and CD15s+). Conclusions: Pre-transplant Treg administration can inhibit alloimmunity within the lung allograft at early time points post- transplant. Our organ-directed approach has potential for clinical translation.

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Section: Resultssupporting

confidence: 89%

Ex vivodelivery of regulatory T cells for control of alloimmune priming in the donor lung

Miyamoto

Takahagi

Ohsumi

et al. 2021

Preprint

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“…This activation is a two-step process. In the first step, IL-2 activates naïve/resting tTreg, and in the presence of alloantigen generates donor-specific activated Treg (28,29,50,51) that express receptors for Type-1 cytokines, including IL-12 and IFN-g (28,29,51). We identified these Ts1 cells by using Type I cytokines to activate CD4 + CD25 + cells from a naïve host in vitro (28,29,51).…”

Section: Discussionmentioning

confidence: 99%

“…In the first step, IL-2 activates naïve/resting tTreg, and in the presence of alloantigen generates donor-specific activated Treg (28,29,50,51) that express receptors for Type-1 cytokines, including IL-12 and IFN-g (28,29,51). We identified these Ts1 cells by using Type I cytokines to activate CD4 + CD25 + cells from a naïve host in vitro (28,29,51). In the second step of activation the phenotype of Ts1 cells can be further modified by stimulation to specific donor alloantigen and IL-12 (28) in the absence of IL-2.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor

Hall

Tran

et al. 2021

Front. Immunol.

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CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25- T cells’ activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed foxp3, irf4, gata3 and il5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p<0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts’ CD4+CD25+ cells expressed more Il5ra and responded to specific donor Lewis but not self. Enriched CD4+CD25+ cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3 and Il5. These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.

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“…Furthermore, if the aforementioned mice are then inoculated with tumor cells originating from the same strain of mouse, potent anti-tumor immune responses are induced [98]. If the proliferation of allografted antigen-specific Treg is attempted in the same experimental system, immunotolerance for the organ graft can be induced [99].…”

Section: Treg and Tumor Immunitymentioning

confidence: 99%

Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges

Kunimasa

Goto

2020

IJMS

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The immune system plays a dual role in tumor evolution—it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline.

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Alloactivation of Naïve CD4+CD8−CD25+T Regulatory Cells: Expression of CD8α Identifies Potent Suppressor Cells That Can Promote Transplant Tolerance Induction

Cited by 10 publications

References 57 publications

Ex vivodelivery of regulatory T cells for control of alloimmune priming in the donor lung

Ex vivodelivery of regulatory T cells for control of alloimmune priming in the donor lung

Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor

Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges

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