CD28 molecule | Elisa - Clia - Antibody - Protein

Background

CD28 is a pivotal co-stimulatory molecule expressed on the surface of T cells. It plays a crucial role in the activation and survival of T cells, which are essential components of the adaptive immune system. CD28 is predominantly found on CD4+ T helper cells, although it is also present on a subset of CD8+ cytotoxic T cells. The interaction of CD28 with its ligands, CD80 (B7-1) and CD86 (B7-2), on antigen-presenting cells (APCs) provides the necessary secondary signals that, together with signals from the T cell receptor (TCR), lead to full T cell activation, proliferation, and differentiation. The presence and function of CD28 are vital for initiating effective immune responses and for maintaining T cell homeostasis and tolerance.

Protein Structure

The CD28 molecule is a homodimeric glycoprotein, each monomer comprising several distinct structural domains:

Extracellular Domain:

• This domain is responsible for ligand binding and consists of approximately 134 amino acids.
• It includes an immunoglobulin variable (IgV)-like domain that interacts with CD80 and CD86.
• The extracellular portion is heavily glycosylated, which is crucial for its stability and ligand binding.

Transmembrane Domain:

• Comprising about 25 hydrophobic amino acids, the transmembrane region anchors CD28 in the cell membrane.
• This region is involved in the dimerization of CD28 monomers, a critical feature for its function.

Cytoplasmic Tail:

• The intracellular domain contains approximately 41 amino acids.
• It has several conserved motifs, including YMNM and PYAP, which are essential for signal transduction.
• These motifs recruit and activate various intracellular signaling molecules, such as PI3K, Grb2, and ITK, upon ligand binding.

Classification and Subtypes

CD28 does not have multiple subtypes like some other cell surface molecules. However, it functions in concert with various co-stimulatory and inhibitory receptors, forming part of a broader family of immune regulatory proteins. Its primary ligands, CD80 and CD86, are expressed on APCs, and their interaction with CD28 is essential for the co-stimulation required for T cell activation.

Function and Biological Significance

T Cell Activation:

• CD28 provides critical second signals necessary for T cell activation. Without these signals, TCR engagement alone may lead to anergy or apoptosis.
• The binding of CD28 to CD80/CD86 on APCs enhances TCR signaling, leading to increased IL-2 production, T cell proliferation, and survival.

Cytokine Production:

• CD28 signaling augments the production of various cytokines, including IL-2, IL-4, and IFN-γ, which are essential for T cell proliferation and differentiation.
• It helps skew the T cell response towards different effector functions depending on the cytokine milieu.

Regulation of Immune Responses:

• CD28 plays a role in maintaining immune tolerance and preventing autoimmunity.
• It is involved in the expansion and function of regulatory T cells (Tregs), which suppress excessive immune responses and maintain self-tolerance.

Costimulation and Immune Checkpoints:

• CD28 works in tandem with inhibitory receptors like CTLA-4, which also binds to CD80/CD86 but delivers inhibitory signals to downregulate T cell responses.
• The balance between CD28 and CTLA-4 signaling is crucial for the proper regulation of immune responses.

Clinical Issues

Autoimmune Diseases:

• Dysregulation of CD28 signaling can contribute to autoimmune diseases. Overactive CD28 signaling may lead to excessive T cell activation and autoimmunity.
• Therapeutic strategies targeting CD28, such as abatacept (a CTLA-4-Ig fusion protein), aim to modulate this pathway to treat autoimmune conditions like rheumatoid arthritis.

Cancer Immunotherapy:

• Enhancing CD28 signaling can boost anti-tumor immunity. This is the basis for using checkpoint inhibitors that block inhibitory receptors like CTLA-4 and PD-1, thus favoring CD28-mediated co-stimulation.
• However, care must be taken to avoid excessive immune activation, which can lead to immune-related adverse events.

Transplantation:

• CD28 signaling is critical in graft rejection. Blocking CD28 or its ligands can promote transplant tolerance.
• Agents like belatacept (another CTLA-4-Ig fusion protein) are used in transplantation to inhibit CD28-mediated T cell activation and prevent rejection.

Infectious Diseases:

• Proper CD28 signaling is essential for effective responses to infections. Impaired CD28 function can lead to inadequate immune responses and increased susceptibility to infections.

Summary

The CD28 molecule is a cornerstone of T cell activation and immune regulation. Its structure, comprising extracellular, transmembrane, and cytoplasmic domains, allows it to interact with ligands CD80 and CD86 on APCs, providing crucial co-stimulatory signals for T cell activation. CD28 signaling enhances cytokine production, promotes T cell proliferation, and helps maintain immune tolerance. Clinically, CD28 is significant in autoimmunity, cancer immunotherapy, transplantation, and infectious diseases. Therapeutic modulation of CD28 signaling, through agents like CTLA-4-Ig fusion proteins, offers promising avenues for treating various immune-related conditions. Understanding CD28's roles and mechanisms is essential for developing targeted immunotherapies and improving immune regulation strategies.