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Review
. 2010 Aug;2(8):a002436.
doi: 10.1101/cshperspect.a002436. Epub 2010 Jun 9.

An enigmatic tail of CD28 signaling

Jonathan S Boomer  1 , Jonathan M Green
Affiliations
Review

An enigmatic tail of CD28 signaling

Jonathan S Boomer et al. Cold Spring Harb Perspect Biol. 2010 Aug.

Abstract

CD28 costimulation regulates a wide range of cellular processes, from proliferation and survival to promoting the differentiation of specialized T-cell subsets. Since first being identified over 20 years ago, CD28 has remained a subject of intense study because of its profound consequences on T cell function and its potential for therapeutic manipulation. In this review we highlight the signaling cascades initiated by the major signaling motifs in CD28, focusing on PI-3 kinase-dependent and -independent pathways and how these are linked to specific cellular outcomes. Recent studies using gene targeted knockin mice have clarified the relative importance of these motifs on in vivo immune responses; however, much remains to be elucidated. Understanding the mechanism behind costimulation holds great potential for development of new clinically relevant reagents, a fact beginning to be realized with the advent of drugs that prevent CD28 ligation and signaling.

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Figures

Figure 1.
Figure 1.
Motif specific protein:protein interactions with the cytoplasmic tail of CD28. Engagement of CD28 by CD80 or CD86 expressed on the antigen presenting cell (APC), initiates signal transduction cascades dependent on specific association of proteins with the cytoplasmic tail of CD28. The proximal YMNM motif when phosphorylated via Src family kinases binds the SH2 containing (indicated in red) proteins p85, a subunit of PI3K, and Grb2 or GADS via their SH2 domain. The distal proline-rich motifs bind the SH3 containing (indicated in blue) proteins Itk, at the sequence PRRP, and Grb2 (via its SH3 domain), filamin-A and Lck at the sequence PYAP.
Figure 2.
Figure 2.
PI3K dependent signal pathway. Tyrosine phosphorylation of the YMNM motif via Src family kinases initiates the binding of the p85 subunit of PI3K. PI3K activity leads to the production of D-3 lipids, which recruit proteins via their pleckstrin homology domain (PH), including PDK1 and PKB/Akt. Once PKB is phosphorylated by PDK1, PKB phosphorylates its downstream targets including mTOR, IκB, GSK3β and Bad. Active mTOR and IκB result in increased NF-κB transcriptional activity whereas the phosphorylation of Bad and GSK3β results in increased survival and NFAT transcriptional regulation, respectively. The activation of NF-κB and NFAT (indicated by the dotted lines) induces the transcription of both Bcl-XL, a prosurvival factor, and IL-2, an important T-cell cytokine required for proliferation as well as other genes.
Figure 3.
Figure 3.
Adaptor protein intiated signaling events. The binding of the adaptor protein Grb2 to CD28 occurs via its SH2 domain at the proximal YMNM motif or its SH3 domain at the distal PYAP motif. Grb2 through an SH3 interaction may subsequently bind Vav which has the potential to initiate two signaling complexes. The Vav-Sos complex results in cdc42/Rac1 activation an initiator of cytoskeletal rearrangement and downstream MAPK activation (JNK) that induces the formation of the AP1 transcriptional complex. Vav also binds the SLP-76-LAT complex, which activates PLCγ1 a kinase that increases intracellular Ca2+, through IP3 production, and activates PKCθ via DAG. The increase in intracellular Ca2+ results in calcineurin activation, a phosphatase that acts on NFAT allowing for its nuclear translocation. PKCθ activation leads to the formation of a multi-protein complex with Bcl10, MALT1 and CARMA-1 that induces NF-κB transcriptional activation. The distal PYAP motif also binds Lck a Src kinase that phosphorylates PDK1 which phosphorylates and activates PKCθ and subsequently inactivates GSK3β via phosphorylation resulting in enhanced transcription of NFAT–dependent genes. Stabilization of cytokine mRNA is also dependent on signals originating at the PYAP through a mechanism that may involve Lck binding (indicated via the dotted arrow) or an unknown protein whereas cytoskeletal rearrangement at the PYAP motif is filamin-A (FLNA) dependent.
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