1. 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.
- Author
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Bulwin GC, Wälter S, Schlawinsky M, Heinemann T, Schulze A, Höhne W, Krause G, Kalka-Moll W, Fraser P, Volk HD, Löhler J, Milford EL, and Utku N
- Subjects
- CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Cell Proliferation, Cells, Cultured, Humans, Lymphocytes cytology, Apoptosis, HLA-DR Antigens metabolism, Inflammation immunology, Lymphocytes immunology, Signal Transduction, Vacuolar Proton-Translocating ATPases metabolism
- 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.
- Published
- 2008
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