# CD4

## Overview
The CD4 gene encodes the CD4 protein, a transmembrane glycoprotein that plays a pivotal role in the immune system. This protein is primarily expressed on the surface of T helper cells, as well as on monocytes, macrophages, and dendritic cells. Functionally, the CD4 protein acts as a co-receptor that enhances T cell receptor (TCR) signaling, which is crucial for T cell activation and differentiation, thereby facilitating adaptive immune responses (Zhu2008CD4). Structurally, the CD4 protein is part of the immunoglobulin superfamily and consists of four extracellular immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail (Ptaszek1994Molecular; Ryu1990Crystal). The CD4 protein is also involved in significant protein-protein interactions, including those with the TCR-CD3 complex and the HIV gp120 envelope glycoprotein, highlighting its role in immune response modulation and its involvement in HIV infection (Glassman2016The; Kwong1998Structure). Alterations in CD4 expression or function can lead to clinical implications, such as impaired immune responses in chronic lymphocytic leukemia and dysregulation in autoimmune and chronic inflammatory diseases (Görgün2005Chronic; Zenewicz2009CD4).

## Structure
The CD4 protein is a glycoprotein expressed on the surface of T cells, playing a crucial role in the immune response. It is composed of four immunoglobulin-like extracellular domains (D1-D4), a transmembrane domain, and a cytoplasmic tail. The primary structure of CD4 includes a sequence of 433 amino acids, with residues 1-371 exposed extracellularly, residues 372-395 within the membrane, and the remaining forming the cytoplasmic tail (Ptaszek1994Molecular).

The secondary structure of CD4 is characterized by β-strands forming immunoglobulin-like domains. The D1 domain is similar to immunoglobulin variable domains, featuring a β-sheet framework with a β sandwich structure, while the D2 domain resembles immunoglobulin constant domains but with unique disulfide bonds (Ryu1990Crystal). The tertiary structure is stabilized by disulfide bonds, contributing to the protein's stability and function (Ryu1990Crystal).

CD4 functions as a monomer, but its quaternary structure involves potential dimeric interactions, although these are unlikely to persist in solution (Ryu1990Crystal). Post-translational modifications include glycosylation, with N-linked glycosylation sites at Asn271 and Asn300, which may influence ligand binding and protein orientation (Yin2012Crystal). The CD4 protein is part of the immunoglobulin superfamily, which generally serves in recognition processes (Ryu1990Crystal).

## Function
The CD4 molecule is a glycoprotein expressed on the surface of immune cells, including T helper cells, monocytes, macrophages, and dendritic cells. It plays a crucial role in the immune system by acting as a co-receptor that enhances T cell receptor (TCR) signaling. This interaction is essential for T cell activation and differentiation, which are vital processes for initiating immune responses and maintaining immune system balance (Zhu2008CD4).

CD4+ T cells are central to adaptive immunity, providing help in both cytotoxic T cell and antibody-mediated responses. They are involved in the differentiation of naive T cells into various effector cells, such as Th1, Th2, Th17, and regulatory T cells (Tregs), each with specific functions and cytokine production patterns (Zhu2008CD4; Geginat2014Plasticity). Th1 cells, for example, produce IFN-γ and are effective against intracellular pathogens, while Th2 cells produce IL-4 and target extracellular parasites (Zhu2008CD4).

The plasticity of CD4+ T cells allows them to acquire new functions upon antigenic re-stimulation, and some can switch between helper and regulatory roles. This plasticity is significant for developing immune-modulatory therapies for chronic infections, autoimmune diseases, and cancer (Geginat2014Plasticity).

## Clinical Significance
Alterations in the expression of the CD4 gene or its interactions can lead to significant clinical implications. Chronic lymphocytic leukemia (CLL) cells can induce changes in the gene expression of CD4 T cells, leading to functional impairments. In CLL patients, CD4 T cells exhibit altered expression of genes involved in pathways such as cytoskeleton formation and vesicle trafficking, which are crucial for T cell differentiation and function. These changes result in decreased Th1 differentiation and a skewing towards Th2 responses, impairing the immune response against tumor cells (Görgün2005Chronic).

The differentiation of CD4 T cells into various subsets, such as Th1, Th2, Th17, and regulatory T cells (Tregs), is essential for immune regulation. Dysregulation in these processes can lead to autoimmune diseases and chronic inflammatory conditions. For instance, Th1 cells are implicated in autoimmune diseases like Crohn's disease, while Th17 cells are associated with chronic inflammatory diseases (Zenewicz2009CD4). The role of CD4 T cells in these conditions underscores the importance of maintaining proper gene expression and interaction to prevent immune-related disorders.

## Interactions
The CD4 molecule is involved in various protein-protein interactions that are crucial for its function in the immune system. CD4 forms stable complexes with several membrane proteins, including CD45, CD71, LPAP, and Lck, on the surface of CEM cells. These interactions are essential for T-cell signaling and function (Krotov2007Profiling). CD4's interaction with CD45 is particularly significant, as it is confirmed through immunoprecipitation, with CD45 being more abundant on CEM cells than CD4. CD71 also co-precipitates with CD4, although reverse precipitation does not show CD4, possibly due to the antibody used (Krotov2007Profiling).

CD4 is also known to interact with the TCR-CD3 complex within a macro-complex involving pMHC. This interaction is facilitated by the proximity of the CD4 juxtamembrane region to the CD3 subunits, which is crucial for T-cell activation (Glassman2016The). Additionally, CD4 interacts with the HIV gp120 envelope glycoprotein, where specific residues in CD4, such as Phe43 and Arg59, make multiple contacts with conserved residues in gp120, highlighting the intricate nature of this interaction (Kwong1998Structure). These interactions underscore CD4's role in immune response modulation and its involvement in HIV infection.


## References


[1. (Ryu1990Crystal) Seong-Eon Ryu, Peter D. Kwong, Alemseged Truneh, Terence G. Porter, James Arthos, Martin Rosenberg, Xiaoping Dai, Nguyen-huu Xuong, Richard Axel, Raymond W. Sweet, and Wayne A. Hendrickson. Crystal structure of an hiv-binding recombinant fragment of human cd4. Nature, 348(6300):419–426, November 1990. URL: http://dx.doi.org/10.1038/348419a0, doi:10.1038/348419a0. This article has 438 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/348419a0)

[2. (Ptaszek1994Molecular) L. M. Ptaszek, S. Vijayakumar, G. Ravishanker, and D. L. Beveridge. Molecular dynamics studies of the human cd4 protein. Biopolymers, 34(9):1145–1153, September 1994. URL: http://dx.doi.org/10.1002/bip.360340904, doi:10.1002/bip.360340904. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/bip.360340904)

[3. (Kwong1998Structure) Peter D. Kwong, Richard Wyatt, James Robinson, Raymond W. Sweet, Joseph Sodroski, and Wayne A. Hendrickson. Structure of an hiv gp120 envelope glycoprotein in complex with the cd4 receptor and a neutralizing human antibody. Nature, 393(6686):648–659, June 1998. URL: http://dx.doi.org/10.1038/31405, doi:10.1038/31405. This article has 2395 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/31405)

[4. (Krotov2007Profiling) G. I. Krotov, M. P. Krutikova, V. G. Zgoda, and A. V. Filatov. Profiling of the cd4 receptor complex proteins. Biochemistry (Moscow), 72(11):1216–1224, November 2007. URL: http://dx.doi.org/10.1134/S0006297907110077, doi:10.1134/s0006297907110077. This article has 13 citations.](https://doi.org/10.1134/S0006297907110077)

[5. (Glassman2016The) Caleb R. Glassman, Heather L. Parrish, Neha R. Deshpande, and Michael S. Kuhns. The cd4 and cd3δε cytosolic juxtamembrane regions are proximal within a compact tcr–cd3–pmhc–cd4 macrocomplex. The Journal of Immunology, 196(11):4713–4722, June 2016. URL: http://dx.doi.org/10.4049/jimmunol.1502110, doi:10.4049/jimmunol.1502110. This article has 15 citations.](https://doi.org/10.4049/jimmunol.1502110)

[6. (Görgün2005Chronic) Güllü Görgün, Tobias A.W. Holderried, David Zahrieh, Donna Neuberg, and John G. Gribben. Chronic lymphocytic leukemia cells induce changes in gene expression of cd4 and cd8 t cells. Journal of Clinical Investigation, 115(7):1797–1805, July 2005. URL: http://dx.doi.org/10.1172/jci24176, doi:10.1172/jci24176. This article has 238 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci24176)

[7. (Zhu2008CD4) Jinfang Zhu and William E. Paul. Cd4 t cells: fates, functions, and faults. Blood, 112(5):1557–1569, September 2008. URL: http://dx.doi.org/10.1182/blood-2008-05-078154, doi:10.1182/blood-2008-05-078154. This article has 1197 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2008-05-078154)

[8. (Yin2012Crystal) Yiyuan Yin, Xin Xiang Wang, and Roy A. Mariuzza. Crystal structure of a complete ternary complex of t-cell receptor, peptide–mhc, and cd4. Proceedings of the National Academy of Sciences, 109(14):5405–5410, March 2012. URL: http://dx.doi.org/10.1073/pnas.1118801109, doi:10.1073/pnas.1118801109. This article has 104 citations.](https://doi.org/10.1073/pnas.1118801109)

[9. (Geginat2014Plasticity) Jens Geginat, Moira Paroni, Stefano Maglie, Johanna Sophie Alfen, Ilko Kastirr, Paola Gruarin, Marco De Simone, Massimiliano Pagani, and Sergio Abrignani. Plasticity of human cd4 t cell subsets. Frontiers in Immunology, December 2014. URL: http://dx.doi.org/10.3389/fimmu.2014.00630, doi:10.3389/fimmu.2014.00630. This article has 208 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2014.00630)

[10. (Zenewicz2009CD4) Lauren A. Zenewicz, Andrey Antov, and Richard A. Flavell. Cd4 t-cell differentiation and inflammatory bowel disease. Trends in Molecular Medicine, 15(5):199–207, May 2009. URL: http://dx.doi.org/10.1016/j.molmed.2009.03.002, doi:10.1016/j.molmed.2009.03.002. This article has 218 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.molmed.2009.03.002)