The signaling through the T-cell receptor complex described in the previous sections is not by itself sufficient to activate a naive T cell. As noted in Chapter 1, antigen-presenting cells that can activate naive T cells bear cell-surface proteins known as co-stimulatory molecules or co-stimulatory ligands. These interact with cell-surface receptors, known as co-stimulatory receptors, on the naive T cell to transmit a signal that is required, along with antigen stimulation, for T-cell activation—this signal is sometimes called ‘signal 2.’ We discuss the immunological consequences of this requirement for co-stimulation in detail in Chapter 9.
The best understood of these co-stimulatory receptors is the cell-surface protein CD28. CD28 is present on the surface of all naive T cells and binds the co-stimulatory ligands B7.1 (CD80) and B7.2 (CD86), which are expressed mainly on specialized antigen-presenting cells such as dendritic cells. To become activated, the naive lymphocyte must engage both antigen and a co-stimulatory ligand on the same antigen-presenting cell. CD28 signaling aids antigen-dependent T-cell activation mainly by promoting T-cell proliferation, cytokine production, and cell survival. All these effects are mediated by signaling motifs present in the cytoplasmic domain of CD28.
After engagement by B7 molecules, CD28 becomes tyrosine phosphorylated by Lck in its cytoplasmic domain on tyrosine residues in a YXN motif that can recruit the adaptor protein Grb2, and in a non-ITAM motif YMNM. The cytoplasmic tail of CD28 also carries a proline-rich motif (PXXP) that binds the SH3 domains of Lck and Itk. Although the details are uncertain, a major effect of CD28 phosphorylation is to activate PI 3-kinase to generate PIP3 (Fig. 7.29). By this mechanism, the co-stimulatory signal induced by CD28 cooperates with the T-cell receptor signal to ensure maximal activation of three of the four T-cell receptor signaling modules described above. Specifically, a high concentration of PIP3 recruits Itk to the membrane, where Lck can phosphorylate it, thereby enhancing PLC-γ activation. PIP3 also functions to recruit and activate Akt, which promotes cell survival and increased cellular metabolism (see Section 7.17). An additional function of Akt is to phosphorylate the RNA-binding protein NF-90; when phosphorylated, NF-90 translocates from the nucleus to the cytoplasm and binds to and stabilizes the IL-2 mRNA, leading to increased IL-2 synthesis. Finally, PIP3 recruits Vav, leading to cytoskeletal reorganization (see Section 7.19). Thus, co-stimulatory signaling through CD28 functions to amplify most of the downstream responses to T-cell receptor stimulation (see Fig. 7.29).
MOVIE 7.3
CD28B7MHCPIP2PIP3PI3KPI3KPIP3 recruits PDK1 and Akt, allowing PDK1 to phosphorylate and activate Akt B7 binding induces CD28 phosphorylation, activating PI 3-kinase to produce PIP3 B7.1 and B7.2 are CD28 ligands expressed on specialized APCs PIP3 also recruits Itk, allowing it to phosphorylate PLC-˜PIP3 also recruits Vav, leading to Cdc24 activation SH2domainkinasedomainAktItkSLP-76LATPDK1PLC-˜activeCdc42inactiveCdc42Vav