The T cell receptor (TCR) is a complex molecule found on the surface of T cells, which play a central role in the immune response. TCRs are crucial for recognizing antigens presented by other cells, thereby initiating the immune response against pathogens or diseased cells. CD4 and CD8 are glycoproteins expressed on the surface of T cells and act as co-receptors that play critical roles in the immune system. They assist the T cell receptor (TCR) in recognizing antigens presented by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs) or infected cells. Both CD4 and CD8 enhance the sensitivity of the T cell response, but they differ in their structure, the populations of T cells on which they are found, and the type of MHC molecules they recognize. Here's a closer look at the structure and function of the T cell receptor and the co-receptors:
Structure
Molecular Composition: The TCR is composed of two chains, typically an alpha (α) chain and a beta (β) chain, although a minority of T cells express gamma (γ) and delta (δ) chains. These chains are linked by a disulfide bond.
Variable (V) and Constant (C) Regions: Each chain consists of a variable (V) region, which is involved in antigen recognition, and a constant (C) region. The variability in the V region allows for the immense diversity of antigens that TCRs can recognize.
CD3 Complex: The αβ or γδ TCR complexes are non-covalently associated with the CD3 complex, composed of several distinct chains (γ, δ, ε, and ζ). The CD3 complex is essential for signal transduction into the T cell following antigen recognition, enabling the cell to respond to the detected antigen.
CD4 co-receptor: CD4 is a single-chain transmembrane glycoprotein composed of four extracellular immunoglobulin-like domains (D1 to D4). Expressed on: CD4 is primarily expressed on the surface of helper T cells (Th cells) and to a lesser extent on monocytes, macrophages, and dendritic cells. CD4 binds to a non-polymorphic region of MHC class II molecules, which are primarily found on antigen-presenting cells such as dendritic cells, B cells, and macrophages. By binding to MHC class II, CD4 facilitates the interaction between the TCR and the MHC-peptide complex, enhancing the activation of the TCR signaling pathway. This interaction is crucial for the activation of CD4+ T cells, which in turn help orchestrate the immune response by producing cytokines, stimulating B cells to produce antibodies, and assisting in the activation of cytotoxic T cells and macrophages.
CD8 co-receptor: CD8 exists either as a homodimer (CD8αα) or more commonly as a heterodimer (CD8αβ), each composed of an α and a β chain, or two α chains, linked by a disulfide bond. Each chain has a single extracellular immunoglobulin-like domain. CD8 is mainly found on the surface of cytotoxic T cells (Tc cells), as well as some subsets of dendritic cells and NK T cells. CD8 binds to a non-polymorphic region of MHC class I molecules, which are expressed on the surface of all nucleated cells. This interaction is key for the activation of CD8+ T cells, enabling them to recognize and kill cells that are infected with viruses or other intracellular pathogens, as well as cancer cells. The binding of CD8 to MHC class I enhances the sensitivity of the TCR for the antigenic peptide presented by MHC class I molecules, facilitating TCR signaling and cytotoxic T cell activation. By binding to MHC molecules, CD4 and CD8 also function as adhesion molecules, stabilizing the interaction between T cells and APCs or target cells.
Function
Antigen Recognition: Unlike antibodies that can recognize antigens in their native form floating free or on the surface of pathogens, TCRs recognize small peptide fragments of antigens. These peptides are presented on the surface of other cells within the groove of Major Histocompatibility Complex (MHC) molecules. CD8+ T cells typically recognize antigens presented by MHC class I molecules (found on almost all nucleated cells), while CD4+ T cells recognize antigens presented by MHC class II molecules (expressed on specialized antigen-presenting cells like dendritic cells, macrophages, and B cells).
Signal Transduction: Upon recognition of the peptide-MHC complex and co-receptor binding to MHC, the TCR transmits a signal inside the T cell through the associated CD3 complex and co-receptors (CD4 or CD8). This signal initiates a cascade of events leading to T cell activation, proliferation, and differentiation into effector cells capable of combating pathogens or infected cells.
Diversity: The diversity of the TCR repertoire is generated through a genetic recombination process known as V(D)J recombination, which randomly rearranges V (variable), D (diversity), and J (joining) gene segments in developing T cells. This process occurs for both the α and β chains (or γ and δ chains), creating a vast array of TCR specificities capable of recognizing many different antigens.
TCRs are instrumental in the adaptive immune response, enabling the immune system to target and remember specific pathogens. The specificity and diversity of the TCR repertoire are key to the effectiveness of this response, allowing for precise targeting of infections and contributing to immune memory, which underlies the principle of vaccination. Understanding TCRs is also crucial for developing targeted immunotherapies, such as T cell receptor-engineered T cells (TCR-T cells) for cancer treatment.
