CD154 explained

CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells^[1] and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and integrin αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (T_FH cells).^[2] On T_FH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication.^[3] A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome.^[4] Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

History

In 1991, three groups reported discovering CD154. Seth Lederman, Michael Yellin, and Leonard Chess at Columbia University generated a murine monoclonal antibody, 5c8, that inhibited contact-dependent T cell helper function in human cells and which characterized a 32 kDa surface protein transiently expressed on activated CD4+ T cells.^[5] Richard Armitage at Immunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig.^[6] Randolph Noelle at Dartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function.^[7] Noelle contested Lederman's patent, but the challenge (called an interference) was rejected on all counts ^[8]

Expression

CD40 ligand (CD154) is primarily expressed on activated CD4+ T lymphocytes but is also found in a soluble form. While CD40L was originally described on T lymphocytes, its expression has since been found on a wide variety of cells, including platelets, mast cells, macrophages, basophils, NK cells, B lymphocytes, as well as non-haematopoietic cells (smooth muscle cells, endothelial cells, and epithelial cells).^[9]

Specific effects on cells

CD40L plays a central role in costimulation and regulation of the immune response via T cell priming and activation of CD40-expressing immune cells.^[10] At least 46 disease-causing mutations in this gene have been discovered.^[11]

Macrophages

In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L on the T cell, which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface, which helps increase the level of activation. The activated macrophage can then destroy phagocytosed bacteria and produce more cytokines.

B cells

B cells can present antigens to a specialized group of helper T cells called T_FH cells. If an activated T_FH cell recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40, causing B cell activation.^[12] The T cell also produces IL-4, which directly influences B cells. As a result of this stimulation, the B cell can undergo rapid cellular division to form a germinal center where antibody isotype switching and affinity maturation occurs, as well as their differentiation to plasma cells and memory B cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target.Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little class switching or germinal centre formation, and immune responses are severely inhibited.^[13]

Endothelial cells

Activation of endothelial cells by CD40L (e.g. from activated platelets) leads to reactive oxygen species production, as well as chemokine and cytokine production, and expression of adhesion molecules such as E-selectin, ICAM-1, and VCAM-1. This inflammatory reaction in endothelial cells promotes recruitment of leukocytes to lesions and may potentially promote atherogenesis.^[14] CD40L has shown to be a potential biomarker for atherosclerotic instability.^[15]

Interactions

CD154 has been shown to interact with RNF128.^[16]

Further reading

• Book: Parham P . The Immune System . Garland Science . 2nd . 2004 . 169–173 . 0-8153-4093-1 . registration .
• Tong AW, Stone MJ . CD40 and the effect of anti-CD40-binding on human multiple myeloma clonogenicity . Leukemia & Lymphoma . 21 . 1–2 . 1–8 . March 1996 . 8907262 . 10.3109/10428199609067572 .
• van Kooten C, Banchereau J . CD40-CD40 ligand . Journal of Leukocyte Biology . 67 . 1 . 2–17 . January 2000 . 10647992 . 10.1002/jlb.67.1.2 . Jacuqes Banchereau . 35592719 .
• Schattner EJ . CD40 ligand in CLL pathogenesis and therapy . Leukemia & Lymphoma . 37 . 5–6 . 461–472 . May 2000 . 11042507 . 10.3109/10428190009058499 . 39398949 .
• Bhushan A, Covey LR . CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes . Immunologic Research . 24 . 3 . 311–324 . 2002 . 11817328 . 10.1385/IR:24:3:311 . 19537892 .
• Book: Cheng G, Schoenberger SP . Signal Transduction Pathways in Autoimmunity . CD40 signaling and autoimmunity . 5 . 51–61 . 2002 . 11826760 . 10.1159/000060547 . 3-8055-7308-1 . Current Directions in Autoimmunity .
• Subauste CS . CD154 and type-1 cytokine response: from hyper IgM syndrome to human immunodeficiency virus infection . The Journal of Infectious Diseases . 185 . Suppl 1 . S83–S89 . February 2002 . 11865444 . 10.1086/338003 . free .
• Kornbluth RS . An expanding role for CD40L and other tumor necrosis factor superfamily ligands in HIV infection . Journal of Hematotherapy & Stem Cell Research . 11 . 5 . 787–801 . October 2002 . 12427285 . 10.1089/152581602760404595 .
• Xu Y, Song G . The role of CD40-CD154 interaction in cell immunoregulation . Journal of Biomedical Science . 11 . 4 . 426–438 . 2005 . 15153777 . 10.1159/000077892 . 202658036 .
• Book: Law CL, Grewal IS . Therapeutic Targets of the TNF Superfamily . Therapeutic Interventions Targeting CD40L (CD154) and CD40: The Opportunities and Challenges . Advances in Experimental Medicine and Biology . 2009. 647. 8–36. 10.1007/978-0-387-89520-8_2. 19760064. 978-0-387-89519-2.

External links

• • • GeneReviews/NCBI/NIH/UW entry on X-Linked Hyper IgM Syndrome or Immunodeficiency with Hyper-IgM, Type 1

Notes and References

1. Lederman S, Yellin MJ, Krichevsky A, Belko J, Lee JJ, Chess L . Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help) . The Journal of Experimental Medicine . 175 . 4 . 1091–1101 . April 1992 . 1348081 . 2119166 . 10.1084/jem.175.4.1091 .
2. Lederman S, Yellin MJ, Inghirami G, Lee JJ, Knowles DM, Chess L . Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help . Journal of Immunology . 149 . 12 . 3817–3826 . December 1992 . 1281189 . 10.4049/jimmunol.149.12.3817 . free .
3. Lederman S, Yellin MJ, Cleary AM, Pernis A, Inghirami G, Cohn LE, Covey LR, Lee JJ, Rothman P, Chess L . T-BAM/CD40-L on helper T lymphocytes augments lymphokine-induced B cell Ig isotype switch recombination and rescues B cells from programmed cell death . Journal of Immunology . 152 . 5 . 2163–2171 . March 1994 . 7907632 . 10.4049/jimmunol.152.5.2163 . 42460521 .
4. Web site: Entrez Gene: CD40LG CD40 ligand (TNF superfamily, member 5, hyper-IgM syndrome).
5. Lederman S, Yellin MJ, Krichevsky A, Belko J, Lee JJ, Chess L . Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help) . The Journal of Experimental Medicine . 175 . 4 . 1091–1101 . April 1992 . 1348081 . 2119166 . 10.1084/jem.175.4.1091 .
6. Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, Macduff BM, Anderson DM, Gimpel SD, Davis-Smith T, Maliszewski CR . Molecular and biological characterization of a murine ligand for CD40 . Nature . 357 . 6373 . 80–82 . May 1992 . 1374165 . 10.1038/357080a0 . 4336943 . 1992Natur.357...80A .
7. Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A . A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells . Proceedings of the National Academy of Sciences of the United States of America . 89 . 14 . 6550–6554 . July 1992 . 1378631 . 49539 . 10.1073/pnas.89.14.6550 . free . 1992PNAS...89.6550N .
8. Web site: Patent 5,474,771. UNITED STATES PATENT AND TRADEMARK OFFICE. U.S. Patent Office. 2016-06-18. https://web.archive.org/web/20160304051007/http://www.uspto.gov/web/offices/dcom/bpai/its/104415-135.pdf. 2016-03-04. dead.
9. Schönbeck U, Libby P . The CD40/CD154 receptor/ligand dyad . Cellular and Molecular Life Sciences . 58 . 1 . 4–43 . January 2001 . 11229815 . 11146501 . 10.1007/PL00000776 . 33085593 . free .
10. Grewal IS, Flavell RA . CD40 and CD154 in cell-mediated immunity . Annual Review of Immunology . 16 . 111–135 . 1998 . 9597126 . 10.1146/annurev.immunol.16.1.111 .
11. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4 . 2019NatSR...918577S .
12. Cleary AM, Fortune SM, Yellin MJ, Chess L, Lederman S . Opposing roles of CD95 (Fas/APO-1) and CD40 in the death and rescue of human low density tonsillar B cells . Journal of Immunology . 155 . 7 . 3329–3337 . October 1995 . 7561026 . 10.4049/jimmunol.155.7.3329 . 39514335 .
13. Grewal IS, Xu J, Flavell RA . Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand . Nature . 378 . 6557 . 617–620 . December 1995 . 8524395 . 10.1038/378617a0 . 4259617 . 1995Natur.378..617G .
14. Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S . New markers of inflammation and endothelial cell activation: Part I . Circulation . 108 . 16 . 1917–1923 . October 2003 . 14568885 . 10.1161/01.CIR.0000089190.95415.9F . free .
15. Wang JH, Zhang YW, Zhang P, Deng BQ, Ding S, Wang ZK, Wu T, Wang J . CD40 ligand as a potential biomarker for atherosclerotic instability . Neurological Research . 35 . 7 . 693–700 . September 2013 . 23561892 . 3770830 . 10.1179/1743132813Y.0000000190 .
16. Lineberry NB, Su LL, Lin JT, Coffey GP, Seroogy CM, Fathman CG . Cutting edge: The transmembrane E3 ligase GRAIL ubiquitinates the costimulatory molecule CD40 ligand during the induction of T cell anergy . Journal of Immunology . 181 . 3 . 1622–1626 . August 2008 . 18641297 . 2853377 . 10.4049/jimmunol.181.3.1622 .