title: HLA-DR alpha 2 mediates negative signalling via binding to Tirc7 leading to anti-inflammatory and apoptotic effects in lymphocytes in vitro and in vivo.
abstract: Classically, HLA-DR expressed on antigen presenting cells (APC) initiates lymphocyte activation via presentation of peptides to TCR bearing CD4+ T-Cells. Here we demonstrate that HLA-DR alpha 2 domain (sHLA-DRalpha2) also induces negative signals by engaging TIRC7 on lymphocytes. This interaction inhibits proliferation and induces apoptosis in CD4+ and CD8+ T-cells via activation of the intrinsic pathway. Proliferation inhibition is associated with SHP-1 recruitment by TIRC7, decreased phosphorylation of STAT4, TCR-zeta chain & ZAP70, and inhibition of IFN-gamma and FasL expression. HLA-DRalpha2 and TIRC7 co-localize at the APC-T cell interaction site. Triggering HLA-DR - TIRC7 pathway demonstrates that sHLA-DRalpha2 treatment inhibits proinflammatory-inflammatory cytokine expression in APC & T cells after lipopolysaccaride (LPS) stimulation in vitro and induces apoptosis in vivo. These results suggest a novel antiproliferative role for HLA-DR mediated via TIRC7, revise the notion of an exclusive stimulatory interaction of HLA-DR with CD4+ T cells and highlights a novel physiologically relevant regulatory pathway.
authors.affiliation: CellAct Pharma GmbH, Berlin, Germany.
authors.forename: Grit-Carsta
authors.initials: GC
authors.lastname: Bulwin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wälter
authors.forename: Mirko
authors.initials: M
authors.lastname: Schlawinsky
authors.forename: Thomas
authors.initials: T
authors.lastname: Heinemann
authors.forename: Anke
authors.initials: A
authors.lastname: Schulze
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.forename: Gerd
authors.initials: G
authors.lastname: Krause
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Kalka-Moll
authors.forename: Patricia
authors.initials: P
authors.lastname: Fraser
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Jürgen
authors.initials: J
authors.lastname: Löhler
authors.forename: Edgar L
authors.initials: EL
authors.lastname: Milford
authors.forename: Nalân
authors.initials: N
authors.lastname: Utku
mesh_terms: D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D006684:HLA-DR Antigens; C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases