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Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation
Esilida Sula Karreci, … , Judy Lieberman, Jamil Azzi
Esilida Sula Karreci, … , Judy Lieberman, Jamil Azzi
Published November 2, 2017
Citation Information: JCI Insight. 2017;2(21):e91599. https://doi.org/10.1172/jci.insight.91599.
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Research Article Immunology Transplantation

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

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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.

Authors

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

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Figure 1

GrB expression among Tregs in the renal allograft of a transplant recipient undergoing rejection.

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GrB expression among Tregs in the renal allograft of a transplant recipi...
Two representative confocal microscopy images (63×) of a kidney allograft biopsy of a patient undergoing clinical rejection. We observed that Tregs characterized by nuclear FoxP3 staining (FITC color, green) coexpressed with cytoplasmic GrB staining (PE color, red). FoxP3, forkhead box P3.

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