TY - JOUR
T1 - Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation
AU - Sula Karreci, Esilida
AU - Eskandari, Siawosh K
AU - Dotiwala, Farokh
AU - Routray, Sujit K
AU - Kurdi, Ahmed T
AU - Assaker, Jean Pierre
AU - Luckyanchykov, Pavlo
AU - Mihali, Albana B
AU - Maarouf, Omar
AU - Borges, Thiago J
AU - Alkhudhayri, Abdullah
AU - Patel, Kruti R
AU - Radwan, Amr
AU - Ghobrial, Irene
AU - McGrath, Martina
AU - Chandraker, Anil
AU - Riella, Leonardo V
AU - Elyaman, Wassim
AU - Abdi, Reza
AU - Lieberman, Judy
AU - Azzi, Jamil
PY - 2017/11/2
Y1 - 2017/11/2
N2 - 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.
AB - 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.
KW - Allografts
KW - Apoptosis
KW - Caspase 3/metabolism
KW - Graft Rejection/immunology
KW - Granzymes/blood
KW - Humans
KW - Immunophenotyping
KW - Kidney Transplantation
KW - Serpins
KW - T-Lymphocytes, Regulatory/cytology
KW - Transplant Recipients
U2 - 10.1172/jci.insight.91599
DO - 10.1172/jci.insight.91599
M3 - Article
C2 - 29093262
SN - 2379-3708
VL - 2
JO - JCI Insight
JF - JCI Insight
IS - 21
M1 - e91599
ER -