title: Serine protease inhibitor-6 differentially affects the survival of effector and memory alloreactive CD8-T cells.
abstract: 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.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: J
authors.initials: J
authors.lastname: Azzi
authors.forename: S
authors.initials: S
authors.lastname: Ohori
authors.forename: C
authors.initials: C
authors.lastname: Ting
authors.forename: M
authors.initials: M
authors.lastname: Uehara
authors.forename: R
authors.initials: R
authors.lastname: Abdoli
authors.forename: B D
authors.initials: BD
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Safa
authors.forename: Z
authors.initials: Z
authors.lastname: Solhjou
authors.forename: P
authors.initials: P
authors.lastname: Lukyanchykov
authors.forename: J
authors.initials: J
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: McGrath
authors.forename: R
authors.initials: R
authors.lastname: Abdi
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002470:Cell Survival / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D053804:Granzymes / Q000502:physiology; D016027:Heart Transplantation; D007156:Immunologic Memory / Q000276:immunology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015843:Serpins / Q000502:physiology*; D016038:Skin Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D015843:Serpins; D053804:Granzymes; C106610:Serpinb9 protein, mouse
keywords: Basic (laboratory) research/science; T cell biology; immunobiology; organ transplantation in general; rejection: T cell-mediated (TCMR)