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

ABSTRACT: Tregs hold great promise as a cellular therapy for multiple immunologically mediated diseases, given their ability to control immune responses. The success of such strategies depends on the expansion of healthy, suppressive Tregs ex vivo and in vivo following the transfer. In clinical studies, levels of transferred Tregs decline sharply in the blood within a few days of the transfer. Tregs have a high rate of apoptosis. Here, we describe a new mechanism of Treg self-inflicted damage. We show that granzymes A and -B (GrA and GrB), which are highly upregulated in human Tregs upon stimulation, leak out of cytotoxic granules to induce cleavage of cytoplasmic and nuclear substrates, precipitating apoptosis in target cells. GrA and GrB substrates were protected from cleavage by inhibiting granzyme activity in vitro. Additionally, we show - by using cytometry by time of flight (CYTOF) - an increase in GrB-expressing Tregs in the peripheral blood and renal allografts of transplant recipients undergoing rejection. These GrB-expressing Tregs showed an activated phenotype but were significantly more apoptotic than non-GrB expressing Tregs. This potentially novel finding improves our understanding of Treg survival and suggests that manipulating Gr expression or activity might be useful for designing more effective Treg therapies.

SUBMITTER: Sula Karreci E

PROVIDER: S-EPMC5690280 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Sula Karreci Esilida E Eskandari Siawosh K SK Dotiwala Farokh F Routray Sujit K SK Kurdi Ahmed T AT Assaker Jean Pierre JP Luckyanchykov Pavlo P Mihali Albana B AB Maarouf Omar O Borges Thiago J TJ Alkhudhayri Abdullah A Patel Kruti R KR Radwan Amr A Ghobrial Irene I McGrath Martina M Chandraker Anil A Riella Leonardo V LV Elyaman Wassim W Abdi Reza R Lieberman Judy J Azzi Jamil J

JCI insight 20171102 21

Tregs hold great promise as a cellular therapy for multiple immunologically mediated diseases, given their ability to control immune responses. The success of such strategies depends on the expansion of healthy, suppressive Tregs ex vivo and in vivo following the transfer. In clinical studies, levels of transferred Tregs decline sharply in the blood within a few days of the transfer. Tregs have a high rate of apoptosis. Here, we describe a new mechanism of Treg self-inflicted damage. We show tha ...[more]

PMID: 29093262

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

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

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