Immune response - CD28 signaling

CD 28 signaling

Induction of immune response requires T cells to receive two sets of signals from antigen-presenting cells. The first signal is delivered via T-cell receptor complex (TCR), while the second one proceeds via co-receptor CD28. TCR and CD28 are independent signaling units. However, Cd28 amplifies signal triggered by TCR ligation [1].

CD28 is a T-cell surface protein activated by interacting with the B-cell activation antigens CD80 and CD86 [2].

In response to ligand activation, CD28 binds with the regulatory subunits of phosphatidylinositol kinase 1 (PIK3R1A), adaptor proteins GRB2 and GRB2-related adaptor protein (GRAP2) and T cell-specific tyrosine kinase ITK [3], [4].

Lck and Fyn are critical for the CD28 co-stimulation. These kinases phosphorylate motifs present in the cytoplasmic tail of CD28, thus enabling it to bind p85 subunit of PI3K and GRB2 [5]. Lck and Fyn also phosphorylate and consequently activate Itk and Vav-1 respectively [1], [6].

CB28 binds with SLP-76 via adaptor proteins GRB2 and GRAP2. SLP-76 recruits VAV-1, linking CD28 to VAV effectors. Mechanism of Vav-1 activation upon CD28 ligation is unclear. Putatively, TCR selectively induces ZAP-70 activation, followed by phosphorylation of the scaffold proteins LAT and SLP-76 [7]. LAT, in turn, can bind to the SLP-76 adaptor via GRB2 and GRAP [8].

Vav-1 exerts pleiotropic effects mediated by the Rho family of guanosine triphosphatases (GTPases). Rac1 is a target for VAV and participates in actin cytoskeletal remodeling.

Additionally, VAV-1 regulates activity of PLC-gamma 1 by facilitating availability of PtdIns(4,5)P2, the PLC-gamma 1 substrate via stimulation of PIP-5 kinase, a Rac1 downstream element [9].

Itk also phosphorylates and activates PLC-gamma 1 [9].

The activated PCL-gamma 1 is responsible for synthesis of second messengers Diacylglycerol (DAG) and Inositol 1,4,5-triphosphate (IP₃) by cleaving Phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) at the plasma membrane. DAG activates a number of proteins, including various isoforms of protein kinase C (PKC). PKC-theta activates kinase IKK, which phosphorylates serine residues on I-kappa-B proteins, thus marking them for destruction via ubiquitination, and, thereby, enabling activation of the NF-kappa-B complex [10].

IP3 binds IP3 Receptor (IP3R), which is localized primarily on the endoplasmic reticulum where it stimulates release of calcium from intracellular stores. Calcium-bound Calmodulin associates with and activates serine/threonine phosphatase Calcineurin. Calcineurin dephosphorylates NF-AT family of transcription factors leading to theirs translocation to the nucleus [11].

Activated PI3K converts PtdIns(4,5)P2 into Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P₃) [12]. CD28 ligation stimulates generation of PtdIns(3,4,5)P₃. PtdIns(3,4,5)P₃ associates with the inner face of the plasma membrane promoting recruitment of proteins with pleckstrin homology (PH) domains, such as ITK, VAV1, and Akt [4]. Akt blocks Glycogen synthase kinase-3 (GSK-3), which phosphorilates NF-AT and, thereby, prevents its nuclear translocation [13].

Additionally, CD28 activates JNK cascade via VAV-1 activation. VAV-1 activates Rac1 and CDC24, which activate JNK via MEKK1 and MKK4/7. Activated JNK phosphorylates transcription factors such as JUN, thereby activating AP1 complex, involved in regulation of cell proliferation [14].

References:

1. Michel F, Acuto O
   CD28 costimulation: a source of Vav-1 for TCR signaling with the help of SLP-76? Science's STKE : signal transduction knowledge environment 2002 Aug 6;2002(144):pe35
2. Slavik JM, Hutchcroft JE, Bierer BE
   CD80 and CD86 are not equivalent in their ability to induce the tyrosine phosphorylation of CD28. The Journal of biological chemistry 1999 Jan 29;274(5):3116-24
3. Marengere LE, Okkenhaug K, Clavreul A, Couez D, Gibson S, Mills GB, Mak TW, Rottapel R
   The SH3 domain of Itk/Emt binds to proline-rich sequences in the cytoplasmic domain of the T cell costimulatory receptor CD28. Journal of immunology (Baltimore, Md. : 1950) 1997 Oct 1;159(7):3220-9
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   Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation. Immunological reviews 2003 Apr;192:32-41
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   Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. The Journal of biological chemistry 1998 Nov 27;273(48):31932-8
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   Molecular modifiers of T cell antigen receptor triggering threshold: the mechanism of CD28 costimulatory receptor. Immunological reviews 2003 Apr;192:21-31
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   CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation. Immunity 2001 Dec;15(6):921-33
9. Bustelo XR
   Vav proteins, adaptors and cell signaling. Oncogene 2001 Oct 1;20(44):6372-81
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11. Hogan PG, Chen L, Nardone J, Rao A
    Transcriptional regulation by calcium, calcineurin, and NFAT. Genes & development 2003 Sep 15;17(18):2205-32
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    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
13. Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR
    L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 1999 Oct 14;401(6754):703-8
14. Rudd CE, Schneider H
    Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nature reviews. Immunology 2003 Jul;3(7):544-56