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