Cluster of differentiation 4 (CD4) is a large glycoprotein anchored to the surface of various white blood cells. It functions as a co-receptor, working with the main cellular receptor to enhance and stabilize signaling between immune cells. The presence and location of CD4 are fundamental to the body’s adaptive immune response, influencing how the immune system coordinates its defense mechanisms. Understanding where CD4 is located provides insight into the specific roles of the cells it inhabits and why these cells are targeted in certain diseases.
Cellular Location on Helper T Cells
The most recognized and abundant location of the CD4 protein is on the surface of T helper cells, often referred to as CD4+ T cells. The presence of this molecule is the defining characteristic used to identify them and differentiate them from other lymphocytes, such as cytotoxic T cells (CD8+). T helper lymphocytes are the central coordinators of the adaptive immune system, responsible for communicating with and activating virtually all other major immune cells.
The high concentration of CD4 facilitates the frequent interactions required for immune surveillance. These cells circulate widely in the blood and lymphatic system, ensuring CD4 is positioned to encounter other immune cells in tissues and lymph nodes. This broad distribution allows for a rapid and systemic immune response.
Expression on Antigen Presenting Cells
CD4 is also expressed, though at lower levels, on professional antigen-presenting cells (APCs), including monocytes, macrophages, and dendritic cells. The presence of CD4 on these APCs influences their specialized roles in immunity. Macrophages engulf pathogens, while dendritic cells specialize in processing and presenting pathogen fragments to T cells.
The function of CD4 on these myeloid cells is less clearly defined than its role on T cells, but its presence is thought to aid in immune-related activities. For instance, CD4 ligation on monocytes can induce expression patterns conducive to macrophage differentiation. The molecule may also contribute to the overall efficiency of antigen presentation.
Role in Immune System Signaling
The location of CD4 on the T helper cell membrane dictates its molecular function as a communication enhancer in the immune response. When a T helper cell encounters an APC, the T-cell Receptor (TCR) binds to the Major Histocompatibility Complex Class II (MHC II) molecule. CD4 acts as a co-receptor by physically binding to a non-polymorphic region of the MHC II molecule. This dual binding stabilizes the weak initial interaction, which is required for T-cell activation.
CD4 is non-covalently associated with an enzyme inside the T cell called Lck, a Src-family tyrosine kinase. When CD4 binds to MHC II, it brings Lck into close proximity with the TCR complex. The Lck enzyme is then able to phosphorylate specific signaling components of the TCR complex, initiating a cascade of intracellular signals. This process effectively amplifies the signal generated by the T-cell Receptor, significantly lowering the threshold required for T-cell activation.
Importance in Pathogen Entry
The location of the CD4 protein on immune cells makes it a target for certain pathogens. The most well-known example is the Human Immunodeficiency Virus (HIV), which exploits CD4 to gain entry into the host cell. The viral envelope protein, known as gp120, has a high affinity for the CD4 molecule. The initial binding of the gp120 protein to the CD4 co-receptor is the first, obligatory step in the viral infection process. This attachment causes a significant structural change in the viral envelope protein, exposing a separate binding site on gp120 that must interact with a secondary receptor on the host cell, typically a chemokine receptor like CCR5 or CXCR4.
This sequential binding to both CD4 and the co-receptor is essential, as it triggers the final step: the fusion of the viral membrane with the host cell membrane. Once fusion occurs, the core of the virus is released into the cell’s cytoplasm, beginning the replication cycle. This tropism for CD4-expressing cells explains why HIV primarily targets and destroys T helper cells, macrophages, and dendritic cells. The systematic depletion of CD4+ T helper cells ultimately leads to the collapse of the adaptive immune system, resulting in the condition known as Acquired Immunodeficiency Syndrome (AIDS).