Inhibitory receptors play key roles in NK cells, T cells, and B cells as well as in other cells of innate immunity. Most but not all inhibitory receptors in the immune system contain ITIM motifs in their cytoplasmic tails that can recruit SH2 domain–containing phosphatases and thus attenuate signaling in a broadly similar manner (Fig. 1). Tyrosine residues on the ITIMs of these receptors can be phosphorylated by SRC family kinases linked to lymphocyte activation and, as described earlier, recruit SH2 domain–containing tyrosine phosphatases such as SHP1 and SHP2 and SH2 domain–containing inositol phosphatase SHIP. SHP1 and SHP2 attenuate tyrosine kinase initiated signaling from activating receptors in NK cells as well as from the BCR and TCR in B and T cells, respectively. SHIP removes phosphate moieties from PIP3, as described earlier, and thus inhibits PI3-kinase activity in B and T lymphocytes, NK cells, and some myeloid cells.
Fig1. Inhibitory signaling in lymphocytes. A schematic depiction shows an inhibitory receptor with an extracellular ligand-binding domain and a cytosolic immunotyrosine-based inhibitory motif (ITIM). Ligand binding results in phosphorylation of the ITIM tyrosine by an SRC family kinase, followed by recruitment of an SH2 domain–containing tyrosine phosphatase that can remove phosphates from signaling intermediates and thus attenuate immune receptor signaling.
In NK cells, inhibitory receptors called killer cell immunoglobulin receptors (KIRs) contain extracellular Ig domains that can recognize class I HLA molecules; a subset of these receptors contains cytosolic ITIM motifs. The CD94/ NKG2A inhibitory receptor binds to an atypical class I MHC molecule called HLA-E, and the NKG2A chain of this dimer contains cytosolic ITIM motifs.
The major inhibitory receptors of T cells are proteins of the CD28 family. They are also called coinhibitors, to contrast them with costimulators. One of these, CTLA-4 (CD152), has a higher affinity than CD28 for B7 proteins and is a competitive inhibitor of B7-CD28 interactions. It inhibits immune responses mainly by blocking and removing B7 molecules from APCs, which are the ligands for the activating receptor, CD28, and not by delivering inhibitory biochemical signals (see Chapter 9). Another inhibitory receptor of the same family is PD-1 (programmed cell death protein-1);. PD-1 contains cytosolic ITIM and ITSM motifs that both contribute to inhibitory signaling in T cells. The ITSM motif, when phosphorylated, recruits the tyrosine phosphatase SHP2, which blocks T-cell activation mediated by the TCR complex and CD28.
FcγRIIB is an important attenuator of signaling in activated B cells as well as in dendritic cells and macrophages. It can bind IgG-containing immune complexes through extracellular Ig domains, and primarily recruits SHIP and antagonizes PI3 kinase signaling. This receptor dampens B-cell activation after antibodies are produced.
