One ITIM-containing receptor is PD-1 (see Fig. 7.33), which is induced transiently on activated T cells, B cells, and myeloid cells. It can bind to the B7-family ligands PD-L1 (programmed death ligand-1, B7-H1) and PD-L2 (programmed death ligand-2, B7-DC). Despite their names, we now understand that these proteins function as ligands for the inhibitory receptor PD-1, rather than acting directly in cell death. PD-L1 is constitutively expressed by a wide variety of cells, whereas PD-L2 expression is induced on antigen-presenting cells during inflammation. Because PD-L1 is expressed constitutively, regulation of PD-1 expression could have a critical role in controlling T-cell responses. For example, signaling by pro-inflammatory cytokines can repress PD-1, thus enhancing the T-cell response. Mice lacking PD-1 gradually develop autoimmunity, presumably because of an inability to regulate T-cell activation. In chronic infections, the widespread expression of PD-1 reduces the effector activity of T cells; this helps to limit potential damage to bystander cells, but at the expense of pathogen clearance.
BTLA contains an ITIM and an ITSM and is expressed on activated T cells and B cells, as well as on some cells of the innate immune system. Unlike other CD28-family members, however, BTLA does not interact with B7 ligands but binds a member of the TNF receptor family; called the herpesvirus entry molecule (HVEM), this receptor is highly expressed on resting T cells and immature dendritic cells. When BTLA and HVEM are co-expressed on the same cell, BTLA utilizes a second mechanism that further inhibits lymphocyte activation. In this configuration, BLTA binds to HVEM and prevents HVEM from binding to alternative partners that would stimulate NFκB-dependent pro-survival signaling pathways downstream of HVEM. Alternatively, when BTLA and HVEM are expressed on different cells, the interaction of these two receptors functions to stimulate the positive pro-survival signal in the HVEM-expressing cell.
Other receptors on B cells and T cells also contain ITIMs and can inhibit cell activation when ligated along with the antigen receptors. One example is the receptor FcγRIIB-1 on B cells, which binds the Fc region of IgG antibodies. As a result, antigens present as immune complexes containing IgG antibodies are poor at activating naive B cells, due to the co-engagement of the B-cell receptor with this inhibitory Fc receptor. The ITIM in FcγRIIB-1 recruits SHIP into a complex with the B-cell receptor to block the actions of PI 3-kinase (Fig. 7.34). Another inhibitory receptor on B cells is CD22, a transmembrane protein that recognizes sialic acid-modified glycoproteins commonly found on mammalian cells but rarely on microbial pathogen surfaces. CD22 contains an ITIM that interacts with SHP, a phosphatase that can dephosphorylate adaptors such as SLP-65 that associate with CD22, thereby inhibiting signaling from the B-cell receptor.
The ITIM motif is also an important motif in signaling by receptors on NK cells that inhibit the killer activity of these cells (see Section 3-26). These inhibitory receptors recognize MHC class I molecules and transmit signals that inhibit the release of the NK cell’s cytotoxic granules when the NK cell recognizes a healthy uninfected cell. In NK cells, ITIM-containing receptors play an important role in setting the threshold for NK cell activation by balancing positive signals from ITAM-containing receptors.
Summary.