CD4, or “Cluster of Differentiation 4,” is a glycoprotein expressed on CD4+ T cells and also found on the surface of other immune cells such as macrophages and dendritic cells. It is crucial for adaptive immunity, particularly in antigen recognition and immune response coordination. CD4 functions as a coreceptor with the T-cell receptor (TCR), binding to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells to initiate an immune response 1,2. CD4 is also the interleukin 16 (IL16) receptor (IL16R) that induces a migratory response in CD4+ T cells.
History of CD4 Discovery
The CD4 protein was identified in the late 1970s. A pivotal discovery came in 1984 when researchers recognized CD4 as a receptor exploited by HIV to infect cells, a finding that shaped the understanding of AIDS pathogenesis. Key contributions came from Dr. Robert C. Gallo and Dr. Luc Montagnier, who identified the virus that targets CD4+ T-cells, causing immune system depletion in AIDS patients2,3.
What Do CD4 Proteins Do?
CD4 proteins primarily function as coreceptors on T-helper cells, enabling these cells to recognize and respond to foreign antigens. They stabilize interactions between the T-cell receptor and MHC class II molecules, enhancing T-helper cell activation, which subsequently activates other immune cells, including CD8+ T-cells and B-cells. This response is essential for adaptive immunity and pathogen clearance1.
What Does CD4 Stand For?
CD4 stands for “Cluster of Differentiation 4,” a classification used to identify distinct surface proteins on immune cells, aiding in the identification of cell types and their roles in immune responses3.
Importance and Function of the CD4 Glycoprotein
What is the Function of the CD4 Glycoprotein?
The primary function of CD4 is to act as a coreceptor in the immune response. It binds to MHC class II molecules, facilitating T-cell activation and cytokine release, which are critical for immune system signaling and pathogen response. The CD4+ T-cells help initiate antibody production by B-cells and activate cytotoxic T-cells, ensuring a coordinated immune defense1,2.
What is CD4 a Marker For?
CD4 serves as a surface marker for CD4+ T cells, and its levels are used to assess immune health, especially in HIV/AIDS patients. HIV specifically targets and depletes CD4+ T-cells, leading to immune system failure. CD4 counts are vital in clinical settings to monitor HIV progression and guide antiretroviral therapy decisions2.
Clinical and Research Applications
CD4 has become central in both research and clinical monitoring:
- HIV/AIDS Monitoring: CD4 counts help monitor immune function in HIV patients, providing an indicator of disease progression and a benchmark for therapy initiation2.
- Autoimmune Disease Research: CD4+ T-cells are implicated in autoimmune conditions like multiple sclerosis and rheumatoid arthritis, where they play roles in excessive or misdirected immune responses1.
- Cancer Immunotherapy: Understanding CD4+ T-cell functions has informed advances in immunotherapies, including adoptive T-cell transfer and CAR-T therapies, which harness T-cells to target cancer cells effectively3.
Special Characteristics of CD4
- Molecular Structure: CD4 is a single-chain glycoprotein with an extracellular region with four immunoglobulin-like (Ig-like) domains, a transmembrane domain, and a cytoplasmic domain. It resembles members of the immunoglobulin superfamily, which includes antibodies, making it structurally suited for immune interactions1.
- HIV Receptor: CD4 acts as the primary receptor for HIV, allowing viral entry into CD4+ T cells. Once bound, the virus enters the cell, causing immune system deterioration and progression toward AIDS2,3.
- Role in T-cell Differentiation: CD4+ T-cells differentiate into various subsets (e.g., Th1, Th2, Th17), each playing unique roles in pathogen response and tissue homeostasis, showcasing the diversity and adaptability of immune responses mediated by CD41.
Other Notable Names
Historically, CD4 has been referred to as the T4 antigen or Leu3, names that originated from early immunological research. In animal models, such as those involving non-human primates, similar molecules are sometimes referred to as W3/25 antigens3.
The CD4 cis-dimer protein from Conigen
Since the CD4 molecule was discovered 5 decades ago, different forms of recombinant CD4 proteins have been developed as research reagents. These CD4 recombinant proteins include 1) monomeric CD4-2D (the extracellular first 2 Ig-like domains); 2) monomeric CD4-4D (extracellular 4 Ig-like domains), and CD4-Ig (CD4-2D fused with IgG Fc at the C-terminus). The CD4 cis-dimer protein from Conigen is a novel recombinant CD4 protein containing the 4 Ig-like domain fused with the dimeric motif at the C-terminus. The CD4 cis-dimer is expressed and purified from HEK293 cells with a post-translational modification similar to the natural protein expression in humans. The CD4 cis-dimer protein significantly enhances the binding to envelope glycoproteins from different HIV-1 subtypes. This CD4 cis-dimer can be a very useful reagent for HIV and immunology research.
References
- Zhu, J., & Paul, W. E. (2010). Heterogeneity and plasticity of T helper cells. Cell Research, 20(1), 4–12. https://doi.org/10.1038/cr.2009.138
- Douek, D. C., Roederer, M., & Koup, R. A. (2009). Emerging concepts in the immunopathogenesis of AIDS. Annual Review of Medicine, 60, 471–484. https://doi.org/10.1146/annurev.med.60.041807.123549
- Dalgleish, A. G., Beverley, P. C., Clapham, P. R., Crawford, D. H., Greaves, M. F., & Weiss, R. A. (1984). The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature, 312(5996), 763–767. https://doi.org/10.1038/312763a0
