7-25 Inhibitory receptors on lymphocytes downregulate immune responses by recruiting protein or lipid phosphatases.
Some other receptors that can inhibit lymphocyte activation possess motifs in their cytoplasmic regions that are known as the immunoreceptor tyrosine-based inhibitory motif (ITIM, consensus sequence [I/V]XYXX[L/I], where X is any amino acid) (Fig. 7.33) or the related immunoreceptor tyrosine-based switch motif (ITSM, consensus sequence TXYXX[V/I]). When the tyrosine in an ITIM or ITSM is phosphorylated, it can recruit either of two inhibitory phosphatases, called SHP (SH2-containing phosphatase) and SHIP (SH2containing inositol phosphatase), via their SH2 domains. SHP is a protein tyrosine phosphatase that removes phosphate groups added by tyrosine kinases to a variety of proteins. SHIP is an inositol phosphatase and removes the phosphate from PIP3 to generate PIP2, thus reversing the recruitment of proteins such as Tec kinases and Akt to the cell membrane and thereby inhibiting signaling.
CD28 B7.1 One dimer of CD28 engages just one dimer of B7 A distinct binding orientation allows one dimer of CTLA-4 to bind two different B7 dimers, providing for high-avidity clustering CTLA-4
Fig. 7.32 CTLA-4 has a higher affinity than CD28 for B7 and engages it in a multivalent orientation. cd28 and cTLa-4 are both expressed as dimers on the cell surface and both bind to two ligands of B7.1, which is a dimer, and B7.2, which is not. however, the orientations of the B7 binding of cd28 and of cTLa-4 differ in a way that contributes to the inhibitory action of cTLa-4. one dimer of cd28 engages just one dimer of B7.1. But one dimer of cTLa-4 binds in such a way that two different dimers of B7.1 are engaged at once, allowing these molecules to cluster into complexes of high avidity. This, and the higher affinity of cTLa-4 for B7 molecules, may give it an advantage in competing for available B7 molecules on an antigen-presenting cell, providing one mechanism by which it could block the co-stimulation of T cells.
B cells, T cells, and NK cells express receptors that contain immunoreceptor tyrosine-based inhibitory motifs
PIR-B Fc˜RIIB-1 CD22 BTLA, KIR2DL KIR3DL PD-1
Fig. 7.33 Some lymphocyte cell-surface receptors contain motifs involved in downregulating activation. Several receptors that transduce signals that inhibit lymphocyte or nK-cell activation contain one or more iTims (immunoreceptor tyrosine-based inhibitory motifs) in their cytoplasmic tails (red rectangles). iTims bind to various phosphatases that, when activated, inhibit signals derived from iTamcontaining receptors.