Immune response - TCR and CD28 co-stimulation in activation of NF-kB

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TCR and CD28 costimulation in activation of NF-kB

The induction of an immune response requires that T cells receive 2 sets of signals from antigen-presenting cells. The first signal is delivered through the T-cell receptor complex, while the second is provided by the B-cell activation antigens CD80 and CD86, by interaction with the T-cell surface molecules, CD28 [1], [2].

The T-cell activation is initiated by the T-cell antigen receptor (TCR), which is comprised of a ligand-binding subunit, the alpha and beta chains, and a signaling subunits, namely the CD3 epsilon, gamma, delta chains and the TCR zeta chain. The physiologic ligand for the TCR is foreign peptide bound to the MHC expressed on antigen-presenting cells (APCs) [3]. CD4 acts as a cellular adhesion molecule binding MHC molecules class II. It stabilizes the interaction of class II MHC-restricted T-cells and antigen-presenting cells expressing an antigen in combination with MHC molecules class II [4].

Upon activation of the TCR, the Src family kinase LCK becomes activated. The activated LCK phosphorylates CD3 chains, which promotes the recruitment and subsequent activation of another tyrosine kinase ZAP-70 [5].

Two known substrates of ZAP-70 are the adapter molecules LAT and SLP-76 [5].

Phosphorylation of tyrosine residues on LAT and SLP-76 results in recruitment of a number of other proteins involved in activation different signaling cascades. One of them is PCL-gamma 1.

Activated PCL-gamma 1 is responsible for the production of the second messengers diacylglycerol [DAG] and inositol 1,4,5-triphosphate [IP3] by cleaving phospha-tidylinositol 4,5 bisphosphate [PI(4,5)P2] at the plasma membrane. DAG activates a number of proteins, including various isoforms of protein kinase C (PKC). It was shown, PKC theta activates kinase IKK, which phosphorylates serine residues on the I-kappa-B (I-kB) proteins and marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B complex (NF-kB) [6].

In response to the activation by ligands CD28, in turn, binds to the tyrosine protein kinase ITK, which phosphorylates LAT and PCL-gamma 1 and, thereby, leads to the NF-kB activation.

In addition, CD28 recruits the regulatory subunit of phosphatidylinositol 3-kinase (PIK3R) that activates phosphatidylinositol 3-kinase (PI3K). PI3K converts phosphatidylinositol 4,5-phosphate to phosphatidylinositol 3,4,5-phosphate [PI(3,4,5)P3]. PI(3,4,5)P3 in turn associates with the inner face of the plasma membrane promoting the recruitment of proteins with pleckstrin homology (PH) domains, one of them is protein kinase AKT. Activated AKT participates in stimulation of NF-kB pathway via IKK [5].

Thus, TCR and CD28 costimulation leads to the activation of the transcription factor NF-kB, which plays a key role in the expression of immune response genes.

References:

  1. Lanier LL, O'Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M
    CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. Journal of immunology (Baltimore, Md. : 1950) 1995 Jan 1;154(1):97-105
  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. Nel AE
    T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. The Journal of allergy and clinical immunology 2002 May;109(5):758-70
  4. Krummel MF, Sjaastad MD, Wülfing C, Davis MM
    Differential clustering of CD4 and CD3zeta during T cell recognition. Science (New York, N.Y.) 2000 Aug 25;289(5483):1349-52
  5. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  6. Tan SL, Parker PJ
    Emerging and diverse roles of protein kinase C in immune cell signalling. The Biochemical journal 2003 Dec 15;376(Pt 3):545-52

  1. Lanier LL, O'Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M
    CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. Journal of immunology (Baltimore, Md. : 1950) 1995 Jan 1;154(1):97-105
  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. Nel AE
    T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. The Journal of allergy and clinical immunology 2002 May;109(5):758-70
  4. Krummel MF, Sjaastad MD, Wülfing C, Davis MM
    Differential clustering of CD4 and CD3zeta during T cell recognition. Science (New York, N.Y.) 2000 Aug 25;289(5483):1349-52
  5. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  6. Tan SL, Parker PJ
    Emerging and diverse roles of protein kinase C in immune cell signalling. The Biochemical journal 2003 Dec 15;376(Pt 3):545-52

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