title: Inhibition of innate co-receptor TREM-1 signaling reduces CD4(+) T cell activation and prolongs cardiac allograft survival.
abstract: The innate receptor "triggering-receptor-expressed-on-myeloid-cells-1" (TREM-1) enhances downstream signaling of "pattern recognition receptor" (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM-1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM-1(+) antigen-presenting cells (APC) on alloreactive CD4(+) lymphocytes. Bm12 donor hearts were transplanted into wild-type MHC-class-II-mismatched C57BL/6J recipient mice. Progressive allograft rejection of bm12-donor hearts with decreased organ function, severe vasculopathy and allograft fibrosis was evident within 4 weeks. TREM-1(+) CD11b(+) MHC-II(+) F4/80(+) CCR2(+) APC and IFNγ-producing CD4(+) cells were detected during chronic rejection. Peptide inhibition of TREM-1 attenuated graft vasculopathy, reduced graft-infiltrating leukocytes and prolonged allograft survival, while being accompanied by sustained low levels of CD4(+) and CD8(+) cell infiltration. Remarkably, temporary inhibition of TREM-1 during early immune activation was sufficient for long-term allograft survival. Mechanistically, TREM-1 inhibition leads to reduced differentiation and proliferation of IFNγ-producing Th1 cells. In conclusion, TREM-1 influences chronic heart rejection by regulating the infiltration and differentiation of CD4(+) lymphocytes.
authors: Department of Surgery, University Medical Center Regensburg, Regensburg, Germany.
authors: G
authors: G
authors: Schiechl
authors: S M
authors: SM
authors: Brunner
authors: R
authors: R
authors: Kesselring
authors: M
authors: M
authors: Martin
authors: P
authors: P
authors: Ruemmele
authors: M
authors: M
authors: Mack
authors: S W
authors: SW
authors: Hirt
authors: H J
authors: HJ
authors: Schlitt
authors: E K
authors: EK
authors: Geissler
authors: S
authors: S
authors: Fichtner-Feigl
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D014184:Transplantation, Homologous; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D012313:RNA