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:
- 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
- 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
- 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
- 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
- Lin J, Weiss A
T cell receptor signalling.
Journal of cell science 2001 Jan;114(Pt 2):243-4
- 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
