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Gene Review

Cd40lg  -  CD40 ligand

Mus musculus

Synonyms: CD154, CD40-L, Cd40L, Cd40l, HIGM1, ...
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Disease relevance of Cd40lg


Psychiatry related information on Cd40lg

  • Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury [7].
  • Immunization with free Id and an IgG-CD40L fusion protein, which was identical in structure to Id-CD40L but lost the Id determinant, resulted in significant lower anti-Id responses, indicating that physical linkage between the tumor antigen and CD40L was required for the optimal immune response [8].
  • Using this new tool of memory T cell analysis, we demonstrate that CD8(+) T cell priming in the absence of T cell help or CD40L specifically alters the generation of the effector memory T cell subset, which appears to be crucial for immediate memory responses and long-term maintenance of effective protective immunity [9].
  • Blockade of the CD40/CD154 pathway enhances T-cell-depleted allogeneic bone marrow engraftment under nonmyeloablative and irradiation-free conditioning therapy [10].

High impact information on Cd40lg

  • CD40-CD154-mediated contact-dependent signals between B and T cells are required for the generation of thymus dependent (TD) humoral immune responses [11].
  • This B cell fate decision is determined by the concerted action of two surface proteins on activated T cells, CD40-and Fas-ligands (CD40L and FasL), whose effects are switched by signals from the B cell antigen receptor (BCR) [12].
  • Foreign antigens that stimulate the BCR acutely cause CD40L and FasL to promote clonal proliferation [12].
  • Here we show a crucial role for host MHC class I-dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a) [13].
  • Additional studies indicate that CD154-specific antibody-induced allograft tolerance is perforin dependent [13].

Chemical compound and disease context of Cd40lg


Biological context of Cd40lg


Anatomical context of Cd40lg


Associations of Cd40lg with chemical compounds

  • In contrast, CD40-/- mutant mice responded normally to the T cell-independent (TI) antigens, 2,4,6-trinitrophenyl (TNP)-LPS and TNP-Ficoll [20].
  • We studied the importance of CD40-CD154 in both responses using the reporter Ag popliteal lymph node assay in which selectively acting drugs generate clearly polarized type 1 (streptozotocin) or type 2 (D-penicillamine, diphenylhydantoin) responses to a constant coinjected Ag in the same mouse strain [22].
  • The effect of IL-4 was particularly noteworthy: this cytokine inhibited (LPS + IFN-gamma)-induced IL-12 production, whereas it potentiated the production of IL-12 induced by CD40L [14].
  • Binding studies with E129/G and E129/A gp39 point mutants showed that this residue does not contribute directly to CD40/gp39 binding but that its substitution with a glycine disrupts the gp39 structure [23].
  • Multiple cytokines sharing the common receptor gamma chain can induce CD154/CD40 ligand expression by human CD4+ T lymphocytes via a cyclosporin A-resistant pathway [24].

Physical interactions of Cd40lg

  • However, primary T cells preactivated via CD3 alone cannot induce B cell proliferation; we have shown previously that costimulation of T cells via CD3 and CD28 stabilizes the expression of the CD40L, which we propose contributes to their capacity to act as competent helper-effector cells [25].

Regulatory relationships of Cd40lg

  • Surprisingly, T cells, from CD40L-deficient mice induce similar levels of B7-1 and B7-2 as do wild-type T cells [26].
  • Previous studies from this laboratory have shown that simultaneous blockade of CD28 and CD40 can prevent this lethal reaction by inhibiting the production of IFN-gamma [27].
  • Moreover, in the presence of gamma interferon, anti-CD40 monoclonal antibody (MAb) activated TNFR-deficient macrophages [28].
  • However, the CD40/CD40L interaction is less important for the generation of enhanced CTL activity than for the expression of an elevated level of B7-2 [29].
  • Signaling through CD40 ligand decreases CD80 expression on murine Langerhans cells and enhances IL-12 p40 production [30].

Other interactions of Cd40lg


Analytical, diagnostic and therapeutic context of Cd40lg


  1. Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Grewal, I.S., Foellmer, H.G., Grewal, K.D., Xu, J., Hardardottir, F., Baron, J.L., Janeway, C.A., Flavell, R.A. Science (1996) [Pubmed]
  2. Recombinant CD40L treatment protects allogeneic murine bone marrow transplant recipients from death caused by herpes simplex virus-1 infection. Beland, J.L., Adler, H., Del-Pan, N.C., Kozlow, W., Sung, J., Fanslow, W., Rimm, I.J. Blood (1998) [Pubmed]
  3. CD40 ligand induces an antileukemia immune response in vivo. Dilloo, D., Brown, M., Roskrow, M., Zhong, W., Holladay, M., Holden, W., Brenner, M. Blood (1997) [Pubmed]
  4. CD40 ligand (CD154) enhances the Th1 and antibody responses to respiratory syncytial virus in the BALB/c mouse. Tripp, R.A., Jones, L., Anderson, L.J., Brown, M.P. J. Immunol. (2000) [Pubmed]
  5. CD40-CD40 ligand costimulation is required for generating antiviral CD4 T cell responses but is dispensable for CD8 T cell responses. Whitmire, J.K., Flavell, R.A., Grewal, I.S., Larsen, C.P., Pearson, T.C., Ahmed, R. J. Immunol. (1999) [Pubmed]
  6. Antitumor activity of an oncolytic adenoviral-CD40 ligand (CD154) transgene construct in human breast cancer cells. Gomes, E.M., Rodrigues, M.S., Phadke, A.P., Butcher, L.D., Starling, C., Chen, S., Chang, D., Hernandez-Alcoceba, R., Newman, J.T., Stone, M.J., Tong, A.W. Clin. Cancer Res. (2009) [Pubmed]
  7. Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury. Calingasan, N.Y., Erdely, H.A., Altar, C.A. Neurobiol. Aging (2002) [Pubmed]
  8. Improved immunogenicity of a self tumor antigen by covalent linkage to CD40 ligand. Huang, H.I., Wu, P.Y., Teo, C.Y., Chen, M.N., Chen, Y.C., Silin, D., Tao, M.H. Int. J. Cancer (2004) [Pubmed]
  9. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Huster, K.M., Busch, V., Schiemann, M., Linkemann, K., Kerksiek, K.M., Wagner, H., Busch, D.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Blockade of the CD40/CD154 pathway enhances T-cell-depleted allogeneic bone marrow engraftment under nonmyeloablative and irradiation-free conditioning therapy. Pan, Y., Luo, B., Sozen, H., Kalscheuer, H., Blazar, B.R., Sutherland, D.E., Hering, B.J., Guo, Z. Transplantation (2003) [Pubmed]
  11. CD40 and CD154 in cell-mediated immunity. Grewal, I.S., Flavell, R.A. Annu. Rev. Immunol. (1998) [Pubmed]
  12. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Rathmell, J.C., Townsend, S.E., Xu, J.C., Flavell, R.A., Goodnow, C.C. Cell (1996) [Pubmed]
  13. NK cells promote islet allograft tolerance via a perforin-dependent mechanism. Beilke, J.N., Kuhl, N.R., Van Kaer, L., Gill, R.G. Nat. Med. (2005) [Pubmed]
  14. Regulation of T cell-dependent and -independent IL-12 production by the three Th2-type cytokines IL-10, IL-6, and IL-4. Takenaka, H., Maruo, S., Yamamoto, N., Wysocka, M., Ono, S., Kobayashi, M., Yagita, H., Okumura, K., Hamaoka, T., Trinchieri, G., Fujiwara, H. J. Leukoc. Biol. (1997) [Pubmed]
  15. The relative contribution of the CD28 and gp39 costimulatory pathways in the clonal expansion and pathogenic acquisition of self-reactive T cells. Griggs, N.D., Agersborg, S.S., Noelle, R.J., Ledbetter, J.A., Linsley, P.S., Tung, K.S. J. Exp. Med. (1996) [Pubmed]
  16. Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-alpha and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice. Alleva, D.G., Pavlovich, R.P., Grant, C., Kaser, S.B., Beller, D.I. Diabetes (2000) [Pubmed]
  17. Blockade of CD40-CD40 ligand protects against renal injury in chronic proteinuric renal disease. Kairaitis, L., Wang, Y., Zheng, L., Tay, Y.C., Wang, Y., Harris, D.C. Kidney Int. (2003) [Pubmed]
  18. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Tan, J., Town, T., Paris, D., Mori, T., Suo, Z., Crawford, F., Mattson, M.P., Flavell, R.A., Mullan, M. Science (1999) [Pubmed]
  19. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions. Van den Eertwegh, A.J., Noelle, R.J., Roy, M., Shepherd, D.M., Aruffo, A., Ledbetter, J.A., Boersma, W.J., Claassen, E. J. Exp. Med. (1993) [Pubmed]
  20. CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. Castigli, E., Alt, F.W., Davidson, L., Bottaro, A., Mizoguchi, E., Bhan, A.K., Geha, R.S. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  21. Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection. Hancock, W.W., Sayegh, M.H., Zheng, X.G., Peach, R., Linsley, P.S., Turka, L.A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  22. Selective requirement for CD40-CD154 in drug-induced type 1 versus type 2 responses to trinitrophenyl-ovalbumin. Nierkens, S., van Helden, P., Bol, M., Bleumink, R., van Kooten, P., Ramdien-Murli, S., Boon, L., Pieters, R. J. Immunol. (2002) [Pubmed]
  23. Identification of residues on CD40 and its ligand which are critical for the receptor-ligand interaction. Bajorath, J., Chalupny, N.J., Marken, J.S., Siadak, A.W., Skonier, J., Gordon, M., Hollenbaugh, D., Noelle, R.J., Ochs, H.D., Aruffo, A. Biochemistry (1995) [Pubmed]
  24. Multiple cytokines sharing the common receptor gamma chain can induce CD154/CD40 ligand expression by human CD4+ T lymphocytes via a cyclosporin A-resistant pathway. Fayen, J.D. Immunology (2001) [Pubmed]
  25. Evidence for a critical role for IL-2 in CD40-mediated activation of naive B cells by primary CD4 T cells. Johnson-Léger, C., Christenson, J.R., Holman, M., Klaus, G.G. J. Immunol. (1998) [Pubmed]
  26. Rapid induction of a novel costimulatory activity on B cells by CD40 ligand. Wu, Y., Xu, J., Shinde, S., Grewal, I., Henderson, T., Flavell, R.A., Liu, Y. Curr. Biol. (1995) [Pubmed]
  27. Contribution of interleukin-12 (IL-12) and the CD28/B7 and CD40/CD40 ligand pathways to the development of a pathological T-cell response in IL-10-deficient mice. Wille, U., Villegas, E.N., Craig, L., Peach, R., Hunter, C.A. Infect. Immun. (2002) [Pubmed]
  28. Activated T cells induce macrophages to produce NO and control Leishmania major in the absence of tumor necrosis factor receptor p55. Nashleanas, M., Scott, P. Infect. Immun. (2000) [Pubmed]
  29. Limited importance of CD40/CD40L interaction in the B7-dependent generation of anti-MOPC-315 cytotoxic T lymphocyte activity by tumor bearer splenic cells stimulated in vitro in the presence of tumor necrosis factor. Kalinichenko, T.V., Mokyr, M.B. Cancer Immunol. Immunother. (1998) [Pubmed]
  30. Signaling through CD40 ligand decreases CD80 expression on murine Langerhans cells and enhances IL-12 p40 production. Sugaya, M., Nakamura, K., Asahina, A., Fujita, H., Tada, Y., Torii, H., Tamaki, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  31. CD40-mediated stimulation contributes to lymphocyte proliferation, antibody production, eosinophilia, and mastocytosis during an in vivo type 2 response, but is not required for T cell IL-4 production. Lu, P., Urban, J.F., Zhou, X.D., Chen, S.J., Madden, K., Moorman, M., Nguyen, H., Morris, S.C., Finkelman, F.D., Gause, W.C. J. Immunol. (1996) [Pubmed]
  32. CD40 ligand acts as a costimulatory signal for neonatal thymic gamma delta T cells. Ramsdell, F., Seaman, M.S., Clifford, K.N., Fanslow, W.C. J. Immunol. (1994) [Pubmed]
  33. Induction of IL-12 p40 messenger RNA expression and IL-12 production of macrophages via CD40-CD40 ligand interaction. Kato, T., Hakamada, R., Yamane, H., Nariuchi, H. J. Immunol. (1996) [Pubmed]
  34. The development of a Th1-type response and resistance to Leishmania major infection in the absence of CD40-CD40L costimulation. Padigel, U.M., Perrin, P.J., Farrell, J.P. J. Immunol. (2001) [Pubmed]
  35. Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis. Shimizu, K., Schönbeck, U., Mach, F., Libby, P., Mitchell, R.N. J. Immunol. (2000) [Pubmed]
  36. CD40/CD40 ligand interactions in the host defense against disseminated Candida albicans infection: the role of macrophage-derived nitric oxide. Netea, M.G., Meer, J.W., Verschueren, I., Kullberg, B.J. Eur. J. Immunol. (2002) [Pubmed]
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