| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥10,300,000 (Direct Cost: ¥10,300,000)
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| Research Abstract |
PD-1 -deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identified PD-1 ligand 1 and 2 (PD-L1 and PD-L2) as ligands for PD-1 by computer-based homology search. Both ligands are expressed on nonlymphoid tissues, such as heart or liver. Engagement of PD-1 by PD-1 ligands leads to the inhibition of T cell receptor mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-ligands are expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon, and activated human and murine dendritic cells. Therefore, the relative levels of inhibitory PD-1 ligands and costimulatory B7-1/B7-2 signals on antigen presenting cells may determine the extent of lymphocyte activation and consequently the threshold between tolerance and autoimmunity.
In addition, we
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also generated chimeric molecules composed of the IgG Fc receptor type IIB extracellular region and the PD-1 cytoplasmic region and expressed them in a B lymphoma cell line, IIA1.6. Coligation of the cytoplasmic region of PD-1 with the B cell receptor (BCR) in IIA1.6 transformants inhibited BCR-mediated growth retardation, and tyrosine phosphorylation of effector molecules, including Ig beta, Syk, phospholipase C-gamma 2 and ERK1/2. Mutagenesis studies indicated that these inhibitory effects do not require the N-terminal tyrosine in the immunoreceptor tyrosine-based inhibitory motif-like sequence, but do require the other tyrosine residue in the C-terminal tail. This tyrosine was phosphorylated and recruited src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) on cologation of PD-1 with BCR. These results show that PD-1 can inhibit BCR signaling by recruiting SHP-2 to its phosphotyrosine and dephosphorylating key signal transducers of BCR signaling.
Taken together, we identified two PD-1 ligands and showed that the inhibitory signal of PD-1 is mediated by SHP-2. Less
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