CD80

CD80 (B7-1), a co-stimulatory molecule expressed on antigen-presenting cells (APCs), is a key regulator of adaptive immunity. As a member of the B7 family of immune checkpoint proteins, CD80 interacts with CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on T cells to either enhance or inhibit T cell activation. This dual role positions CD80 as a critical therapeutic target for modulating immune responses in autoimmune diseases, cancer and transplant rejection. Despite its discovery more than three decades ago, the therapeutic use of CD80 remains underexplored compared to other immune checkpoints such as PD-1 or CTLA-4.

NCBI Gene ID: 941

UniProtKB ID: P33681

Cluster of Differentiation (CD) Molecules

Cluster of Differentiation (CD) molecules are cell surface proteins that play a critical role in immune cell identification, signaling, and communication. These molecules are expressed primarily on leukocytes and other immune-related cells and serve as markers to distinguish different cell types, activation states, and functional subsets.

The CD nomenclature was established to standardize the classification of surface antigens on immune cells. Each CD number (e.g., CD4, CD8, CD80) corresponds to a specific protein with a defined function. Some key roles of CD molecules include:

• Cell Signaling: Many CD molecules, such as CD3 on T cells, are involved in signaling for immune activation
• Cell Adhesion: Molecules like CD11/CD18 facilitate immune cell interactions and migration.
• Immune Regulation: CD80 and CD86 provide co-stimulatory signals for T cell activation, while CD25 is a marker for regulatory T cells.
• Disease Markers and Therapeutic Targets: Certain CD molecules, such as CD20 on B cells, serve as drug targets for diseases like leukemia and lymphoma.

Structure and Function of CD80

CD80 is a 60 kDa transmembrane glycoprotein consisting of an extracellular immunoglobulin variable (IgV)-like domain, a constant (IgC)-like domain, a transmembrane region, and a short cytoplasmic tail. It is expressed primarily on activated APCs, including dendritic cells (DCs), macrophages, and B cells. CD80's interaction with CD28 on naive T cells provides a critical co-stimulatory signal required for T cell activation, proliferation, and cytokine production. Conversely, binding to CTLA-4 (expressed on regulatory T cells [Tregs] and activated T cells) transmits an inhibitory signal that dampens immune responses. This dual ligand interaction allows CD80 to act as a "rheostat" of T cell activity, balancing immune activation and tolerance.

CD80 in Immune Homeostasis and Disease

• Autoimmunity: Dysregulated CD80 expression contributes to aberrant T-cell activation in autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Overexpression of CD80 on APCs in inflamed tissues exacerbates pathogenic T-cell responses.
• Cancer: Tumors often exploit CD80's inhibitory axis by upregulating CTLA-4 on T cells or expressing CD80 themselves to induce T-cell exhaustion.
• Transplant Rejection: CD80-mediated co-stimulation drives alloreactive T-cell responses against grafted tissues, making it a target in immunosuppressive regimens.

Figure 1. Influence of CD80 in modulating the activity of cancer cells. When a normal cell presents peptide in context with an MHC molecule to T cells, delivery of CD80 signal generates an effective immune response (A). Efficient presentation of peptide in association with MHC but in absence of costimulation induces immunological ignorance in T cells and immune evasion in cancer cells (B). Presentation of tumor-peptide-MHC complex and expression of CD80 on tumor cells leads to its apoptosis and elicitation of antitumor immunity by the activation of T cells and bidirectional signaling (↔) through the CD80 molecule (C). (Mir et al., 2008)

Rationale for Targeting CD80

Therapeutic Opportunities

• Autoimmune Diseases: CD80 plays a critical role in T cell co-stimulation by binding to CD28, leading to T cell activation and pro-inflammatory cytokine production. In autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS) and systemic lupus erythematosus (SLE), excessive T-cell activation contributes to chronic inflammation and tissue damage. Therapeutic strategies that focus on blocking CD80-CD28 interactions using monoclonal antibodies or fusion proteins (e.g., abatacept and belatacept) aim to reduce aberrant immune activation and alleviate disease symptoms.
• Cancer: The role of CD80 in cancer is complex due to its interactions with both CD28 (stimulatory) and CTLA-4 (inhibitory) receptors. Some tumors exploit the CD80-CTLA-4 axis to suppress anti-tumor immune responses, leading to immune evasion. Enhancing CD80-CTLA-4 interactions may further inhibit T-cell activity and allow tumors to grow unchecked. Conversely, blocking CTLA-4 with immune checkpoint inhibitors (e.g., ipilimumab) or boosting CD80-CD28 signaling could enhance T-cell responses and improve anti-tumor immunity. Combination therapies that modulate CD80 expression or function are actively being explored to improve the efficacy of cancer immunotherapy.
• Transplantation: Alloreactive T cells recognize foreign tissue and trigger graft rejection through CD80-mediated co-stimulation. By targeting CD80, particularly with fusion proteins such as belatacept, it is possible to block CD28 signaling, thereby reducing T-cell activation and prolonging graft survival. This strategy is particularly relevant in kidney and liver transplantation, where immunosuppressive regimens aim to balance immune tolerance while minimizing complications associated with broad immunosuppression.

Advantages Over Other Checkpoints

Unlike PD-1/PD-L1 inhibitors, which primarily target exhausted T cells in the tumor microenvironment, CD80 modulation affects earlier stages of T-cell activation, offering broader control over immune responses.

CD80-Targeted Therapies: Mechanisms and Clinical Progress

Abatacept

Abatacept, a fusion protein combining the extracellular domain of CTLA-4 with the Fc region of IgG1, binds CD80 and CD86 on APCs with high affinity, preventing their interaction with CD28 on T cells. This blockade inhibits the co-stimulatory signal required for T-cell activation, effectively suppressing inflammatory responses.

Belatacept

Belatacept is another recombinant fusion protein designed to selectively inhibit CD80/CD86-mediated T-cell co-stimulation, thereby reducing immune activation. It consists of the extracellular domain of human CTLA-4 fused to the Fc region of human IgG1. This structural design enhances stability and prolongs the half-life of the drug in circulation.

Creative BioMart is proud to supply abatacept and belatacept and thousands of other therapeutic proteins, if you have any questions, please contact us.

References

1. Girard T, Gaucher D, El-Far M, Breton G, Sékaly RP. CD80 and CD86 IgC domains are important for quaternary structure, receptor binding and co-signaling function. Immunology Letters. 2014;161(1):65-75. doi:10.1016/j.imlet.2014.05.002
2. Li L, Yang L, Jiang D. Research progress of CD80 in the development of immunotherapy drugs. Front Immunol. 2024;15. doi:10.3389/fimmu.2024.1496992
3. Mir MA, Agrewala JN. Signaling through CD80: an approach for treating lymphomas. Expert Opinion on Therapeutic Targets. 2008;12(8):969-979.