Abstract
PD-1 is an immunoreceptor that belongs to the immunoglobulin (Ig) superfamily and contains two tyrosine residues in the cytoplasmic region. Studies on PD-1-deficient mice have shown that PD-1 plays critical roles in establishment and/or maintenance of peripheral tolerance, but the mode of action is totally unknown. To study the molecular mechanism for negative regulation of lymphocytes through the PD-1 receptor, we generated chimeric molecules composed of the IgG Fc receptor type IIB (Fc gamma RIIB) 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, Ca(2+) mobilization, and tyrosine phosphorylation of effector molecules, including Ig beta, Syk, phospholipase C-gamma 2 (PLC gamma 2), and ERK1/2, whereas phosphorylation of Lyn and Dok was not affected. 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 coligation 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.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Antigens, CD / genetics
- Antigens, CD / metabolism
- Antigens, Surface / genetics
- Antigens, Surface / metabolism*
- Apoptosis Regulatory Proteins
- Calcium / metabolism
- Cell Division
- Humans
- Intracellular Signaling Peptides and Proteins
- Mice
- Mitogen-Activated Protein Kinase 1 / metabolism
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinases / metabolism
- Phosphorylation
- Phosphotyrosine / metabolism*
- Programmed Cell Death 1 Receptor
- Protein Phosphatase 2
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
- Protein Tyrosine Phosphatases / metabolism*
- Receptors, Antigen, B-Cell / metabolism*
- Receptors, IgG / genetics
- Receptors, IgG / metabolism
- Receptors, Immunologic / genetics
- Receptors, Immunologic / metabolism*
- Receptors, KIR
- SH2 Domain-Containing Protein Tyrosine Phosphatases
- Signal Transduction*
- Tumor Cells, Cultured
- Tyrosine / metabolism
- src Homology Domains*
Substances
- Antigens, CD
- Antigens, Surface
- Apoptosis Regulatory Proteins
- Fc gamma receptor IIB
- Intracellular Signaling Peptides and Proteins
- PDCD1 protein, human
- Pdcd1 protein, mouse
- Programmed Cell Death 1 Receptor
- Receptors, Antigen, B-Cell
- Receptors, IgG
- Receptors, Immunologic
- Receptors, KIR
- Phosphotyrosine
- Tyrosine
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinases
- Protein Phosphatase 2
- PTPN11 protein, human
- PTPN6 protein, human
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
- Protein Tyrosine Phosphatases
- Ptpn11 protein, mouse
- Ptpn6 protein, mouse
- SH2 Domain-Containing Protein Tyrosine Phosphatases
- Calcium