Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation

Karreci, Esilida Sula; Eskandari, Siawosh K.; Dotiwala, Farokh; Routray, Sujit; Kurdi, Ahmed T.; Assaker, Jean Pierre; Luckyanchykov, Pavlo; Mihali, Albana B; Maarouf, Omar H.; Borges, Thiago J.; Alkhudhayri, Abdullah; Patel, Kruti; Radwan, Amr; Ghobrial, Irène M.; McGrath, Martina M.; Chandraker, Anil; Riella, Leonardo V.; Elyaman, Wassim; Abdi, Reza; Lieberman, Judy; Azzi, Jamil

doi:10.1172/jci.insight.91599

Cited by 31 publications

(28 citation statements)

References 65 publications

(75 reference statements)

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“…However, upon changes in plasma membrane potential induced by galectin-9/VISTA, granzyme B release from T cells is most likely affected. Similar effects were described in regulatory T cells (Tregs) (43) and NK cells (39) where granzyme B was shown to leak from cytotoxic granules and induce self-inflicted damage and programmed cell death.…”

Section: Discussionmentioning

confidence: 55%

Ligand-Receptor Interactions of Galectin-9 and VISTA Suppress Human T Lymphocyte Cytotoxic Activity

et al. 2020

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Acute myeloid leukemia (AML), a blood/bone marrow cancer, is a severe and often fatal malignancy. AML cells are capable of impairing the anti-cancer activities of cytotoxic lymphoid cells. This includes the inactivation of natural killer (NK) cells and killing of T lymphocytes. Here we report for the first time that V-domain Ig-containing suppressor of T cell activation (VISTA), a protein expressed by T cells, recognizes galectin-9 secreted by AML cells as a ligand. Importantly, we found that soluble VISTA released by AML cells enhances the effect of galectin-9, most likely by forming multiprotein complexes on the surface of T cells and possibly creating a molecular barrier. These events cause changes in the plasma membrane potential of T cells leading to activation of granzyme B inside cytotoxic T cells, resulting in apoptosis.

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Section: Discussionmentioning

confidence: 55%

Ligand-Receptor Interactions of Galectin-9 and VISTA Suppress Human T Lymphocyte Cytotoxic Activity

et al. 2020

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“…Various studies have demonstrated the marked increase of Tregs in the intestinal mucosa during the active phase of CD [12] . As it mentioned, Tregs can perform their suppressive roles through the four different pathways and suppress the inflammatory disorders such as CD by affecting Teffs [31,37,[41][42][43][44][45][46]53] . There may also be some unexplored suppressive mechanisms used by the Tregs.…”

Section: Suppression By Modulation Of Apc Functionmentioning

confidence: 99%

“…Granzymes can activate various death pathways. For instance, they can cause the cell death (apoptosis) in Teff cells through the caspase-dependent or -independent pathways [43][44][45][46] . Signaling by Fas can also result inapoptosis.…”

Section: Suppression By Cytolysismentioning

confidence: 99%

Suppressive Mechanisms Induced by Tregs in Celiac Disease

Asri

Rostami-Nejad

Barzegar

et al. 2020

ibj

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CD is a systemic immune-mediated disorder caused by the dietary gluten in individuals who are genetically susceptible to the disease. In fact, CD is a T cell-mediated immune disease in which gluten-derived peptides activate the lamina propria CD4 + Teff cells, and these T-cell subsets can cause the intestinal tissue damages. Also, there are additional subsets of CD4 + T cells with suppressor functions. These subsets express the master transcription factor, FOXP3, and include Tr1 cells and CD4 + CD25 + Tregs, which are the main population involved in maintaining the peripheral tolerance, preventing the autoimmune diseases and limiting the chronic inflammatory diseases such as CD. The suppressive function of Tregs is important to maintain the immune homeostasis. This paper examined the features and the basic mechanisms used by Tregs to mediate the suppression in CD.

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“…CyTOF has been used to analyze leukemia samples, showing for the first time that the surface markers of leukemic blasts do not necessarily reflect their intracellular signaling (Levine et al 2015). This approach was recently applied to analyze the malignant or immune composition of acute lymphoblastic leukemia, ovarian carcinoma, renal cancer, hepatocellular carcinoma, and melanoma (Chevrier et al 2017, Chew et al 2017, Gonzalez et al 2018, Good et al 2018, Lavin et al 2017, Sula Karreci et al 2017, Wei et al 2017. Furthermore, this method has been modified to preserve spatial information when applied to tissues (see Section 4.2) (Giesen et al 2014).…”

Section: Protein Profilingmentioning

confidence: 99%

Deciphering Human Tumor Biology by Single-Cell Expression Profiling

Tirosh

Suvà

2019

Annu. Rev. Cancer Biol.

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Human tumors are complex ecosystems where diverse cancer and noncancer cells interact to determine tumor biology and response to therapies. Genomic and transcriptomic methods have traditionally profiled these intricate ecosystems as bulk samples, thereby masking individual cellular programs and the variability among them. Recent advances in single-cell profiling have paved the way for studying tumors at the resolution of individual cells, providing a compelling strategy to bridge gaps in our understanding of human tumors. Here, we review methodologies for single-cell expression profiling of tumors and the initial studies deploying them in clinical contexts. We highlight how these studies uncover new biology and provide insights into drug resistance, stem cell programs, metastasis, and tumor classifications. We also discuss areas of technology development in single-cell genomics that provide new tools to address key questions in cancer biology. These emerging studies and technologies have the potential to revolutionize our understanding and management of human malignancies.

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Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation

Cited by 31 publications

References 65 publications

Ligand-Receptor Interactions of Galectin-9 and VISTA Suppress Human T Lymphocyte Cytotoxic Activity

Ligand-Receptor Interactions of Galectin-9 and VISTA Suppress Human T Lymphocyte Cytotoxic Activity

Suppressive Mechanisms Induced by Tregs in Celiac Disease

Deciphering Human Tumor Biology by Single-Cell Expression Profiling

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