Like CD8, CD4 is a transmembrane glycoprotein that acts as a coreceptor for the T cell receptor (TCR) . Like the TCR, CD4 binds to major histocompatibility complex (MHC) molecules but is specific for MHC class II proteins. The CD4 coreceptor plays a role in T cell signaling alongside the TCR and assists in T helper cell (ThC) -antigen interactions.
(Data source Glatzová D, et al. FrontImmunol. 2019)
Definition and structure of CD4:
CD4 has four immunoglobulin domains (D1 to D4) exposed on the extracellular surface: D1 is similar to the immunoglobulin variable (IgV) domain. D2, D3, and D4 are similar to the immunoglobulin constant (IgC2) domain. CD4 interacts with the β2 domain of MHC class II molecules through its D1 domain. CD4 is primarily expressed on the surface of T lymphocytes and serves as a molecular marker for helper T cells.
(Data source: Tak W, et al. The Immune Response, 2006)
Regulation of immune response:
The close proximity between the TCR complex and CD4 allows the tyrosine kinase Lck to bind to the cytoplasmic tail of CD4, thereby phosphorylating tyrosine residues of the immunoreceptor tyrosine-based activation motif (ITAM) on the cytoplasmic domain of CD3 , amplifying the signal generated by the TCR. Phosphorylated ITAMs on CD3 recruit and activate SH2 domain-containing protein tyrosine kinases (PTKs), such as ZAP70 , which further mediate downstream signaling through tyrosine phosphorylation. These signals lead to the activation of transcription factors, including NF-κB, NFAT, and AP-1, thereby promoting T cell activation.
(Data source: Archives of Microbiology & Immunology 3(2019):133-150.）
Cell differentiation:
CD4+ T cells, as key components of the immune system, play a central role in orchestrating adaptive immune responses. Five major CD4+ T helper (Th) cell subsets have been identified: Th1, Th2, Th17, Treg (regulatory T), and Tfh (follicular helper T) cells. Th1 cells are defined by the expression of the lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, and are involved in type 1 immune responses against intracellular pathogens such as mycobacteria and viruses; Th2 cells are defined by the expression of the lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GATA3, and are involved in type 2 immune responses against larger extracellular pathogens such as helminths; Th17 cells are defined by the expression of the lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, and are involved in type 3 immune responses against extracellular pathogens including some bacteria and fungi; Tfh cells help B cells produce corresponding antibodies by producing IL-21 and expressing Bcl6; and Treg cells expressing Foxp3, unlike Th1/Th2/Th17/Tfh cells that perform effector functions, can regulate immune responses to maintain immune cell homeostasis and prevent immunopathology.
(Data source: Künzli M, et al. Nat Immunol. 2023)
Diseases & Clinical Applications:
The CD4 protein is one of the primary receptors for HIV, and HIV infection primarily occurs by binding to CD4 proteins and invading CD4+ T cells. Understanding CD4+ T cell counts helps monitor the immune status of HIV-infected patients. Furthermore, the application of CD4+ T cells in immunotherapy can be expanded to CAR-T cell therapy.
(Data source: Bhoj VG, et al. Discov Med. 2016)
CD4 continues to be expressed in most tumors derived from T helper cells. CD4 immunohistochemistry is used on tissue biopsy samples to identify most forms of peripheral T-cell lymphomas and related malignancies. This antigen is also associated with many autoimmune diseases . Further understanding of the function and regulation of CD4+ T cell subsets is expected to provide more targets for personalized treatment.
