CD28

Official Full Name

CD28 molecule

Organism

Homo sapiens

GeneID

940

Background

The protein encoded by this gene is essential for T-cell proliferation and survival, cytokine production, and T-helper type-2 development. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

Synonyms

Tp44; IMD123;

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Detailed Information

CD28 is the receptor of B7 molecules (CD80 and CD86), which are expressed on activated antigen presenting cells, and provide necessary signals for full T cell activation. Over the years, it has become clear that CD28 signals do not act solely to amplify T cell receptor (TCR) signaling, but control a wide range of processes, including epigenetic modifications, cell cycle, metabolism, and post-translational modifications. For T cells, CD28 costimulation greatly enhances the response to antigen. It stabilizes the immune synapse, reduces the number of TCR-antigen engagements required to reach the cell's activation threshold, and in keeping with the fundamental postulates of the two-signal model, enables T cell activation and survival. CD28 engagement on CD4 T cells increases the T cell sensitivity to antigen receptors, greatly increases the cytokine production (mostly IL-2), and promotes cell survival through inducing expression of anti-apoptotic proteins including Bcl-XL.

Figure 1. Signaling Pathways Downstream of CD28. (Esensten J H, et al. 2016)

Molecular Mechanisms and Signaling Pathways

Two models have been proposed for ligand-induced receptor triggering and the induction of downstream signaling from monovalent ligand-binding receptors. The first model involves the binding of CD28 to its ligands CD80 and CD86 on the surface of the APCs. The structure and affinity of the two CD28 ligands are different. CD80 has a higher affinity for CD28 and has a tendency to form non-covalent dimers, both in the crystal structure and when expressed at the cell surface. In contrast, CD86 both crystalizes and is mainly expressed at the cell surface as a monomer. Therefore, interaction with dimeric CD80 has the potential to cross-link two monovalent CD28 dimers, while interaction with CD86 cannot. However, both CD80 and CD86 have been shown to be able to induce CD28 signaling and some evidence suggests that CD28 preferentially interacts with the monomeric ligand, CD86.

An alternative model for CD28 ligand binding is that in the case of plasma membrane expression, T cell receptor (TCR) signaling may induce a conformational change in CD28 that allows for bivalent binding. The results show that TCR signaling can also induce a change in the orientation of the cytosolic domains within the CD28 dimer and can enhance CD28 ligand binding. During T cell activation, CD28 may undergo a reorientation of the extracellular dimer interface, allowing divalent ligand binding. CD28 dimers that contain only a single functional ligand binding site are poorly recruited to the immunological synapse. In the context of cell-cell interactions, this change from monovalent to bivalent binding can lead to a >100-fold increase in effective receptor-ligand binding. Therefore, TCR-induced increase in valency could lead to an increase in the avidity of CD28 ligand binding and could explain the enhanced CD28 ligand binding, cross-linking, triggering, and initiation of downstream signaling.

CD28 and Human Disease

A large number of literatures show that CD28 and CTLA4 are critical regulators of autoimmune disease and tolerance to solid organ transplants in mouse models. CD28 expression decreases on human T cells as part of normal aging with CD8⁺ T cells more significantly affected. These cells represent a group of antigen-experienced cells that might have either pro- or anti-inflammatory characteristics. In solid organ transplant recipients, CD8⁺CD28^- cells have been found to undergo oligoclonal expansion and could a suppressive role and promote allograft tolerance. In fact, in kidney transplant recipients, CD8⁺CD28⁻ T cells might be protective against organ rejection, implying a possible immunosuppressive role for this subset.

Increased numbers of circulating oligoclonal CD4⁺CD28^- T cells have been reported in autoinflammatory and autoimmune conditions such as rheumatoid arthritis and multiple sclerosis. These cells can also be found infiltrating into tissue affected by autoimmune processes. CD4⁺CD28^- cells are also elevated in diverse conditions including chronic kidney graft rejection, acute coronary syndrome, and cytomegalovirus infection. The cells produce interferon gamma and cytotoxic proteins perforin and granzyme B. Chronic antigenic stimulation might be related to the loss of CD28 on CD4⁺ T cells given that cytomegalovirus responsiveness is 30-fold more common among CD4⁺CD28^- cells than among CD4⁺CD28⁺ cells.

References:

Esensten J H, et al. CD28 costimulation: from mechanism to therapy. Immunity, 2016, 44(5): 973-988.
Beyersdorf N, et al. CD28 co-stimulation in T-cell homeostasis: a recent perspective. ImmunoTargets and therapy, 2015, 4: 111.
Leddon S A, et al. The CD28 transmembrane domain contains an essential dimerization motif. Frontiers in immunology, 2020, 11: 1519.
Mou D, et al. CD28 negative T cells: is their loss our gain?. American Journal of Transplantation, 2014, 14(11): 2460-2466.
Geltink R I K, et al. Mitochondrial priming by CD28. Cell, 2017, 171(2): 385-397. e11.

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