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Serine Protease Inhibitor‐6 Differentially Affects the Survival of Effector and Memory Alloreactive CD8‐T Cells
Author(s) -
Azzi J.,
Ohori S.,
Ting C.,
Uehara M.,
Abdoli R.,
Smith B. D.,
Safa K.,
Solhjou Z.,
Lukyanchykov P.,
Patel J.,
McGrath M.,
Abdi R.
Publication year - 2015
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13051
Subject(s) - cytotoxic t cell , cd8 , effector , granzyme b , transplantation , adoptive cell transfer , immunology , biology , microbiology and biotechnology , cancer research , t cell , immune system , medicine , in vitro , genetics
The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme‐B (GrB), they also express cytoplasmic serine protease inhibitor‐6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8‐T cells and subsequent generation of memory CD8‐T cells in transplantation. CD8‐T cells from Spi6 −/− mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6 −/− CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8‐T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short‐lived‐effector‐CD8‐cells but did not impact the pool of memory‐precursor‐effector‐CD8‐cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8‐memory‐pool‐size is independent from the initial clonal‐proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells.