CD117 (c-Kit) Is Expressed During CD8+ T Cell Priming and Stratifies Sensitivity to Apoptosis According to Strength of TCR Engagement

Frumento, Guido; Zuo, Jianmin; Verma, Kriti; Croft, Wayne; Ramagiri, Pradeep; Chen, Frederick; Moss, Paul

doi:10.3389/fimmu.2019.00468

Cited by 21 publications

(23 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CD117 molecule is involved in the maintenance of HSC population in the blood and bone marrow. Expression of CD117 decreases during differentiation of immune cells, remaining only in mature neutrophils and some CD8 + T lymphocytes [3]. These findings suggest that thymalin in the course of short-term culturing stimulates the expression of CD117 on HSC, which can be considered as the initial stage of cell differentiation.…”

Section: Resultsmentioning

confidence: 78%

“…Activation of neutrophil growth factor receptor signaling pathway induces proliferation and early stages of HSC differentiation. Activation of CD117 receptor by neutrophil growth factor potentiates a number of cytokine-dependent signaling pathways, thereby promoting proliferation and differentiation of HSC [3,12]. The CD117 molecule is involved in the maintenance of HSC population in the blood and bone marrow.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

et al. 2020

View full text Add to dashboard Cite

Thymalin is a polypeptide complex isolated from the thymus and regulating the functions of the immune system. Thymalin is effective in therapy of acute respiratory syndrome, chronic obstructive bronchitis, and other immunopathology. Thymalin increases functional activity of T lymphocytes, but the targeted molecular mechanism of its biological activity requires further study. We studied the influence of thymalin on differentiation of human hematopoietic stem cells (HSC) and expression of CD28 molecule involved in the implementation of antiviral immunity in COVID-19 infection. It was found that thymalin reduced the expression of CD44 (stem cell marker) and CD117 (molecule of the intermediate stage of HSC differentiation) by 2-3 times and increased the expression of CD28 (marker of mature T lymphocytes) by 6.8 times. This indirectly indicates that thymalin stimulated differentiation of CD117 + cells into mature CD28 + T lymphocytes. It is known that in patients with severe COVID-19, the number of CD28 + , CD4 + , CD8 + T lymphocytes in the blood decreased, which attested to a pronounced suppression of immunity. It is possible that the antiviral effect of thymalin consists in compensatory stimulation of HSC differentiation into CD28 + T lymphocytes at the stage of immunity suppression in unfavorable course of viral infection. Thymalin can be considered as an immunoprotective peptide drug for the prevention of COVID-19.

show abstract

Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…CD117 expression, in contrast, is associated with an immature cell phenotype ( 40 ). CD117 is involved in stem cell differentiation and is generally lost as progenitor cells differentiate into mature blood cells, with the exception of dendritic and mast cells ( 49 – 51 ). The significance of the observed decrease in CD33 and increase in CD45RA is less clear.…”

Section: Discussionmentioning

confidence: 99%

Ascorbate Inhibits Proliferation and Promotes Myeloid Differentiation in TP53-Mutant Leukemia

et al. 2021

View full text Add to dashboard Cite

Loss-of-function mutations in the DNA demethylase TET2 are associated with the dysregulation of hematopoietic stem cell differentiation and arise in approximately 10% of de novo acute myeloid leukemia (AML). TET2 mutations coexist with other mutations in AML, including TP53 mutations, which can indicate a particularly poor prognosis. Ascorbate can function as an epigenetic therapeutic in pathological contexts involving heterozygous TET2 mutations by restoring TET2 activity. How this response is affected when myeloid leukemia cells harbor mutations in both TET2 and TP53 is unknown. Therefore, we examined the effects of ascorbate on the SKM-1 AML cell line that has mutated TET2 and TP53. Sustained treatment with ascorbate inhibited proliferation and promoted the differentiation of these cells. Furthermore, ascorbate treatment significantly increased 5-hydroxymethylcytosine, suggesting increased TET activity as the likely mechanism. We also investigated whether ascorbate affected the cytotoxicity of Prima-1Met, a drug that reactivates some p53 mutants and is currently in clinical trials for AML. We found that the addition of ascorbate had a minimal effect on Prima-1Met–induced cytotoxicity, with small increases or decreases in cytotoxicity being observed depending on the timing of treatment. Collectively, these data suggest that ascorbate could exert a beneficial anti-proliferative effect on AML cells harboring both TET2 and TP53 mutations whilst not interfering with targeted cytotoxic therapies such as Prima-1Met.

show abstract

“…Our studies highlight that there is much to discover in the repertoire of receptors expressed by T cells, especially in non-resting activated states. Indeed, a recent discovery by Frumento et al highlights that activated CD8 + T cells express c-KIT, an RTK of the same family as FLT3, and that its function is inherently tied to T cell priming and propensity to apoptosis [48]. With the rapid development of a new generation of RTKIs, it is important to consider the impacts these potent inhibitors may have on anti-tumor immune responses.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8+ T Cells

et al. 2021

View full text Add to dashboard Cite

There is an increasing interest in the development of Receptor Tyrosine Kinases inhibitors (RTKIs) for cancer treatment, as dysregulation of RTK expression can govern oncogenesis. Among the newer generations of RTKIs, many target Mer Tyrosine Kinase (MERTK) and Fms related RTK 3 (FLT3). Next to being overexpressed in many cancers, MERTK and FLT3 have important roles in immune cell development and function. In this study, we address how the new generation and potent RTKIs of MERTK/FLT3 affect human primary CD8+ T cell function. Using ex vivo T cell receptor (TCR)-activated CD8+ T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8+ T proliferation at the G2 phase, at least in part by modulation of mTOR signaling. Cytokine production and activation remain largely unaffected. Finally, we show that activated CD8+ T cells express FLT3 from day two post activation, and FLT3 inhibition with AC220 (quizartinib) or siRNA-mediated knockdown affects cell cycle kinetics. These results signify that caution is needed when using potent RTKIs in the context of antitumor immune responses.

show abstract

CD117 (c-Kit) Is Expressed During CD8+ T Cell Priming and Stratifies Sensitivity to Apoptosis According to Strength of TCR Engagement

Cited by 21 publications

References 52 publications

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

Ascorbate Inhibits Proliferation and Promotes Myeloid Differentiation in TP53-Mutant Leukemia

Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8+ T Cells

Contact Info

Product

Resources

About