| Literature References | 1. LEE, K.P., TAYLOR, C., PETRYNIA, B., TURKA, L.A., JUNE, C.H. AND
THOMPSON, C.B.
The genomic organization of the CD28 gene. Implication for the
regulation of CD28 mRNA expression and heterogeneity.
J.IMMUNOL. 145 344-352 (1990).
2. GROSS, J.A., JOHN, T. AND ALLISON, J.P.
The murine homologue of the T lymphocyte antigen CD28. Molecular
cloning and cell surface expression.
J.IMMUNOL. 144 3201-3210 (1990).
3. MITTRUCKER, H.W., KURSAR, M., KOHLER, A., HURWITZ, R. AND
KAUFMANN, S.H.E.
Role oF CD28 for the generation and expansion of antigen-specific
CD8+ T lymphocytes during infection with Listeria monocytogenes.
J.IMMUNOL. 167 5620-5627 (2001).
4. SURESH, M., WHITMIRE, J.K., HARRINGTON, L.E., LARSEN, C.P.,
PEARSON, T.C., ALTMAN, J.D. AND AHMED, R.
Role of CD28-B7 interactions in generation and maintenance of CD28 T
cell memory.
J.IMMUNOL. 167 5565-5573 (2001).
5. APPLEMAN, L.J., PUIJENBROEK, A.A.F.L., SHU, K.M., NADLER, L.M.
AND BOUSSIOTIS, V.A.
CD28 costimulation mediates down-regulation of p27kip1 and cell
cycle progression by activation of the P13K/PKB signaling pathway in
primaty human T cells.
J.IMMUNOL. 168 2729-2736 (2002).
6. FRAUWIRTH, K.A. AND THOMPSON, C.B.
Activation and inhibition of lymphocytes by costimulation.
J.CLIN.INVEST. 109 295-299 (2002).
7. CARRENO, B.M. AND COLLINS, M.
The B7 family of ligands and its receptors: new pathways for
costimulation and inhibition of immune responses.
ANNU.REV.IMMUNOL. 20 29-53 (2002).
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| Documentation | Antigen (Ag) recognition by the T cell receptor (TCR) induces activation of
T lymphocytes. However, TCR-mediated signals alone are insufficient for
efficient T cell activation, and additional co-stimulatory signals are
required. One of the most important surface molecules that delivers
co-stimulatory signals for T cells is CD28. The human T lymphocyte Ag CD28
(Tp44) is a homodimeric 90kDa glycoprotein expressed on the surface of the
majority of human peripheral T cells and lymphocytes. Stimulation of CD4+ T
cells in the absence of CD28 co-signalling causes impaired proliferation,
reduced cytokine production and altered generation of helper T cell subsets.
Co-stimulation via CD28 promotes T cell viability, clonal expansion,
cytokine production and effector functions, while also regulating apoptosis
of activated T cells, suggesting its importance in regulating long-term T
cell survival [1-4].
Ligands for CD28 and the structurally related CTLA-4 (CD152) are the
molecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed on
professional antigen presenting cells (APCs) and their expression is up-
regulated during an immune response. Ligation of CD28 by its natural ligands
results in tyrosine phosphorylation at a YMNM motif within its cytoplasmic
tail. The phosphorylated motif subsequently interacts with the Src homology
2 domain in the p85 regulatory subunit of P13K, activating the p110
catalytic subunit. One of the P13K-dependent downstream targets, resulting
from the antibody cross-linking of CD28, is the phoshporylation and
activation of Akt (or PKB). Constitutively active Akt is able to substitute
for CD28 signals, and stimulates IL-2 production when introduced into mature
CD28-deficient cells. Another molecule affected by CD28 stimulation is the
proto-oncogene Vav, which acts as a guanine-nucleotide exchange factor for
Rac and CDC42, allowing these molecules to switch from the inactive GDP-
bound state to the active GTP-bound state [5,6].
Another interesting feature of CD28, is its ability to induce expression of
PDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP has
been reported to affect nearly every pathway important for lymphocyte
activation, leading to inhibition of T cell proliferation. Specifically,
increased intracellular cAMP has been implicated in the induction of T cell
anergy, a non-responsive state that occurs after T cells are stimulated
through TCR/CD3 in the absence of co-stimulation. This can have therapeutic
implications, in that blockage of CD28 co-stimulation can be profoundly
immunosuppressive, preventing induction of pathogenic T cell responses in
autoimmune disease models, and allowing for prolonged acceptance of
allografts in models of organ transplantation [6].
Finally, CD28 co-stimulation directly controls T cell cycle progression by
down-regulating the cdk inhibitor p27kip1, which actually integrates
mitogenic MEK and P13K-dependent signals from both TCR and CD28 [5].
B7 ligands bind to both activating CD28 and inhibitory CTLA-4 (CD152)
receptors. Expression of both receptors and ligands is tightly regulated,
allowing discrimination between signals that result in activation or
inhibition of an immune response. CTLA-4 shares about 30% amino acid
identity with CD28, and both bind to B7-1 and B7-2 ligands. However, the
interaction of CD28 with its ligand is weaker than the interaction of
CTLA-4. Crystal structures of CTLA-4-B7 complexes are characterised by
homodimers of CTLA-4 that contain B-7 binding sites located distantly to
the CTLA-4 dimer interface, suggesting that CTLA-4 homodimers can bind to
noncovalent homodimers of B7-1 or B7-2 to form a lattice of CTLA-4-B7
interactions. CD28 also forms homodimers, with a conserved cysteine located
proximal to the transmembrane domain linking the monomers in CD28 and
CTLA-4. By similarity, CD28 may also form lattice structures with B7-1 and
B7-2, which could serve to potentiate the co-stimulatory signals delivered
through CD28 [7].
CD28ANTIGEN is a 4-element fingerprint that provides a signature for the
CD28 antigen family of proteins. The fingerprint was derived from an initial
alignment of 7 sequences: the motifs were drawn from conserved regions
largely spanning the C-terminal portion of the alignment. Two iterations on
SPTR39_17f were required to reach convergence, at which point a true set
comprising 18 sequences was identified.
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