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.
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.
Bulwin
Grit-Carsta
GC
CellAct Pharma GmbH, Berlin, Germany.
Wälter
Stephanie
S
Schlawinsky
Mirko
M
Heinemann
Thomas
T
Schulze
Anke
A
Höhne
Wolfgang
W
Krause
Gerd
G
Kalka-Moll
Wiltrud
W
Fraser
Patricia
P
Volk
Hans-Dieter
HD
Löhler
Jürgen
J
Milford
Edgar L
EL
Utku
Nalân
N
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*
D006684:HLA-DR Antigens; C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases