title: Mixed hematopoietic or T-cell chimerism above a minimal threshold restores perforin-dependent immune regulation in perforin-deficient mice.
abstract: Defects in perforin and related genes lead to a loss of normal immune regulation and underlie hemophagocytic lymphohistiocytosis (HLH), which requires hematopoietic cell transplantation for long-term cure. However, transplantation may be complicated by the development of mixed chimerism and uncertainty regarding the risk of HLH recurrence. To help clarify this risk and investigate how perforin influences immune activation, we studied perforin-mediated immune regulation in the context of mixed chimerism using a murine model of HLH. We found that there is a distinct threshold of ∼10% to 20% perforin expression with either mixed hematopoietic or CD8(+) T cell chimerism, above which immune regulation was reestablished. These findings demonstrate that perforin-mediated immunoregulation functions in trans and are consistent with a feedback model in which cytotoxic T cells control immune activation by killing dendritic cells. These findings also suggest rational targets for maintenance of minimal posttransplant chimerism and for therapeutic strategies involving gene correction.
authors: Divisions of Cellular and Molecular Immunology, and.
authors: Catherine E
authors: CE
authors: Terrell
authors: Michael B
authors: MB
authors: Jordan
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D018183:Transplantation Chimera
chemical_list: D052899:Pore Forming Cytotoxic Proteins; C510467:perforin 1, mouse; D054353:Perforin
references: Eur J Immunol. 2012 Jun;42(6):1488-99
references: 22678903
references: EMBO Mol Med. 2009 May;1(2):112-24
references: 20049711
references: Blood. 2010 Dec 23;116(26):5824-31
references: 20855862
references: Blood. 2011 Oct 27;118(17):4620-9
references: 21878672
references: Bone Marrow Transplant. 2008 Aug;42(3):175-80
references: 18454181
references: Blood. 2011 Oct 13;118(15):4041-52
references: 21828139
references: Blood. 2011 Oct 27;118(17):4577-84
references: 21900192
references: Blood. 2011 Jun 16;117(24):6582-8
references: 21551232
references: Blood. 2013 Jun 27;121(26):5184-91
references: 23660960
references: Blood. 2004 Aug 1;104(3):735-43
references: 15069016
references: Blood. 2011 Jul 21;118(3):618-26
references: 21606480
references: Br J Haematol. 2005 Aug;130(3):404-8
references: 16042690
references: Pediatrics. 2006 Apr;117(4):e743-50
references: 16549504
references: Blood. 2006 Feb 1;107(3):1233-6
references: 16219800
references: Blood. 2013 Jan 24;121(4):595-603
references: 23160464
references: Bone Marrow Transplant. 2008 Oct;42 Suppl 2:S47-50
references: 18978744
references: Br J Haematol. 2011 Sep;154(5):556-63
references: 21707584