The Abundance and Availability of Cytokine Receptor IL-2Rβ (CD122) Constrain the Lymphopenia-Induced Homeostatic Proliferation of Naive CD4 T Cells

Keller, Hilary R.; Kim, Hye Kyung; Jo, Yuna; Gress, Ronald E.; Hong, Changwan; Park, Jung Hyun

doi:10.4049/jimmunol.1901276

Cited by 12 publications

(12 citation statements)

References 62 publications

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“…IL-2 stimulation will result in increased levels of pSTAT5 in Foxp3 + CD4 T cells, but not in Foxp3-negative conventional CD4 T cells. As previously reported ( Cho et al., 2010 ; Keller et al., 2020 ; Waickman et al., 2020 ), conventional CD4 T cells express only low levels of IL-2Rβ and they are poor responders to IL-2. Foxp3 + Treg cells, on the other hand, express large amounts of IL-2 receptors and they are highly effective in responding to IL-2.…”

Section: Expected Outcomessupporting

confidence: 79%

Assessing IL-2-Induced STAT5 Phosphorylation in Fixed, Permeabilized Foxp3+ Treg Cells by Multiparameter Flow Cytometry

Park

2020

STAR Protocols

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Summary Assessing IL-2-induced phosopho-STAT5 (pSTAT5) content can reveal the cytokine responsiveness of individual T cells. Identifying distinct T cell subsets by nuclear transcription factors, such as Foxp3, and concurrently quantifying intracellular pSTAT5, however, has been technically challenging. Conventional Foxp3 staining buffers quench pSTAT5 signals, while commonly used pSTAT5 staining protocols fail to detect Foxp3. The current protocol resolves these issues by describing a procedure to assess IL-2-induced pSTAT5 contents in Foxp3 + CD4 Treg cells using multiparameter flow cytometry. For complete details on the use and execution of this protocol, please refer to Waickman et al. (2020) .

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Section: Expected Outcomessupporting

confidence: 79%

Assessing IL-2-Induced STAT5 Phosphorylation in Fixed, Permeabilized Foxp3+ Treg Cells by Multiparameter Flow Cytometry

Park

2020

STAR Protocols

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“…Graft-derived conventional T cells expand through lymphopenia-induced homeostatic proliferation and response to host's allogeneic antigens. However, not all T cells respond with the same efficiency to these proliferative cues (32).…”

Section: / Mait Cell Reconstitution Is Delayed For Several Years After Hsctmentioning

confidence: 99%

Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy

Tourret

Talvard-Balland

Lambert

et al. 2021

Preprint

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BackgroundMucosal associated invariant T (MAIT) cells are semi-invariant T cells that recognize microbial antigens presented by the highly conserved MR1 molecule. MAIT cells are predominantly localized in the liver and barrier tissues and are potent effectors of anti - microbial defense. MAIT cells are very few at birth and accumulate gradually over a period of about 6 years during infancy. The cytotoxic potential of MAIT cells, as well as their newly described regulatory and tissue repair functions, open the possibility of exploiting their properties in adoptive therapy. A prerequisite for their use as “universal” cells would be a lack of alloreactive potential, which remains to be demonstrated.MethodsWe used ex vivo, in vitro and in vivo models to determine if human MAIT cells contribute to allogeneic responses.ResultsWe show that recovery of MAIT cells after allogeneic hematopoietic stem cell transplantation recapitulates their slow physiological expansion in early childhood, independent of recovery of conventional T cells. In vitro, signals provided by allogeneic cells and cytokines do not induce sustained MAIT cell proliferation. In vivo, human MAIT cells do not expand nor accumulate in tissues in a model of T-cell mediated xenogeneic graft-versus-host disease (GVHD) in immunodeficient mice.ConclusionsAltogether, these results provide evidence that MAIT cells are devoid of alloreactive potential and pave the way for harnessing their translational potential in universal adoptive therapy overcoming barriers of HLA disparity.

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“… 25 Another drawback is that CD122/CD132-directed IL-2s have limited potential to expand and enhance tumor-reactive CD4 + T cells, which also express low levels of CD122, and as discussed above importantly contribute to antitumor immunity. 26 IL-2-based biologics that shift the selectivity of IL-2 toward the high-affinity IL-2R (CD25/CD122/CD132) circumvent this issue by augmenting specificity toward CD25, which allows for the targeting of recently activated CD4 + and CD8 + Teff cells. A disadvantage of these type of IL-2s is off-target expansion of Tregs, which constitutively express the high-affinity IL-2R.…”

Section: Introductionmentioning

confidence: 99%

High-dose IL-2/CD25 fusion protein amplifies vaccine-induced CD4⁺and CD8⁺neoantigen-specific T cells to promote antitumor immunity

Hernandez

LaPorte

Hsiung

et al. 2021

J Immunother Cancer

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BackgroundImmunization with tumor neoantigens is a promising vaccine approach to promote antitumor immunity due to their high immunogenicity, lack of expression in normal tissue, and preferential induction of tumor neoantigen-specific T cells, which are central mediators of the anti-cancer response. A drawback to targeting tumor neoantigen-specific T cells is that these cells are found at a low frequency in patients with cancer, limiting their therapeutic benefit. Interleukin-2 (IL-2) promotes expansion and persistence of tumor-reactive T cells. However, its clinical use has been hampered by toxicities arising from its multiple cellular targets. Thus, new engineered IL-2 receptor (IL-2R) agonists with distinctive cell type selectivity have been designed to harness the potential of IL-2 for tumor immunotherapy.MethodsWe investigated the potential to amplify neoantigen-specific CD4+ and CD8+ T cell immune responses to promote antitumor immunity through vaccination with tumor neoantigens. Following T cell receptor (TCR)-mediated induction of the high-affinity IL-2R on these T cells, amplification of the neoantigen-specific T cell response was achieved using a high dose of the mouse IL-2/CD25 (mIL-2/CD25) fusion protein, an IL-2R agonist with more favorable pharmacokinetics and pharmacodynamics than IL-2 and selectivity toward the high-affinity IL-2R.ResultsAdministration of a high dose of mIL-2/CD25 shortly after antigen-dependent induction of the high-affinity IL-2R amplified the numbers and function of TCR transgenic tumor-reactive tyrosinase-related protein-1 (TRP-1) CD4+ T cells, leading to antitumor immunity to B16-F10 melanoma. This approach was adapted to amplify endogenous polyclonal B16-F10 neoantigen-specific T cells. Maximal expansion of these cells required prime/boost neoantigen vaccinations, where mIL-2/CD25 was optimal when administered only after the boosting steps. The ensuing mIL-2/CD25-driven immune response supported antitumor immunity to B16-F10 and was more effective than treatment with a similar amount of IL-2. Optimal antitumor effects required amplification of CD4+ and CD8+ neoantigen-specific T cells. High-dose mIL-2/CD25 supported a tumor microenvironment with higher numbers of CD4+ and CD8+ T effectors cells with increased granzyme B expression and importantly a more robust expansion of neoantigen-specific T cells.ConclusionThese results indicate that neoantigen-based vaccines are optimized by potentiating IL-2R signaling in CD4+ and CD8+ neoantigen-reactive T cells by using high-dose mIL-2/CD25, leading to more effective tumor clearance.

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The Abundance and Availability of Cytokine Receptor IL-2Rβ (CD122) Constrain the Lymphopenia-Induced Homeostatic Proliferation of Naive CD4 T Cells

Cited by 12 publications

References 62 publications

Assessing IL-2-Induced STAT5 Phosphorylation in Fixed, Permeabilized Foxp3+ Treg Cells by Multiparameter Flow Cytometry

Assessing IL-2-Induced STAT5 Phosphorylation in Fixed, Permeabilized Foxp3+ Treg Cells by Multiparameter Flow Cytometry

Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy

High-dose IL-2/CD25 fusion protein amplifies vaccine-induced CD4⁺and CD8⁺neoantigen-specific T cells to promote antitumor immunity

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The Abundance and Availability of Cytokine Receptor IL-2Rβ (CD122) Constrain the Lymphopenia-Induced Homeostatic Proliferation of Naive CD4 T Cells

Cited by 12 publications

References 62 publications

Assessing IL-2-Induced STAT5 Phosphorylation in Fixed, Permeabilized Foxp3+ Treg Cells by Multiparameter Flow Cytometry

Assessing IL-2-Induced STAT5 Phosphorylation in Fixed, Permeabilized Foxp3+ Treg Cells by Multiparameter Flow Cytometry

Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy

High-dose IL-2/CD25 fusion protein amplifies vaccine-induced CD4+and CD8+neoantigen-specific T cells to promote antitumor immunity

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Product

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High-dose IL-2/CD25 fusion protein amplifies vaccine-induced CD4⁺and CD8⁺neoantigen-specific T cells to promote antitumor immunity