Abstract
CD154 (CD40-ligand) has a wide variety of pleiotropic effects throughout the immune system and is critical to both cellular and humoral immunity. Cell surface and soluble CD154 are primarily expressed by activated CD4 T cells. Expression of CD154 is tightly regulated in a time-dependent manner, and, like most T cell-derived cytokines and other members of the tumor necrosis factor (GNF) superfamily, CD154 is largely regulated at the level of gene transcription. Recently, dysregulated expression of CD154 has been noted in a number of autoimmune disorders, including systemic lupus erythematosus (SLE). In addition, abnormal expression of CD154 has been hypothesized to contribute to a wider array of diseases, from atherosclerosis to Alzheimer's disease. Until recently, very little was known about the transcriptional regulation of CD154. We are exploring CD154 regulation in primary human CD4 T cells in hopes of understanding the cis- and trans-regulatory elements that control its expression in the cells that normally express CD154. Ultimately, we hope to be able to correct abnormal expression of CD154 in various disease states and to help design gene therapy vectors for treating CD154-deficient individuals with hyper-IgM syndrome.
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References
Van Kooten C, Banchereau J: CD40-CD40 ligand: a multifunctional receptor-ligand pair. Adv Immunol 1996;61:1–77.
Banchereau J, Bazan F, Blanchand D, Briere F, Galizzi JP, van Kooten C, et al.: The CD40 antigen and its ligand. Annu Rev Immunol 1994; 12:881–922.
Karmann K, Hughes CC, Fanslow WC, Pober JS: Endothelial cells augment the expression of CD40 ligand on newly activated human CD4+ T cells through a CD2/LFA-3 signaling pathway. Eur J Immunol 1996;26:610–617.
Grewal IS, Flavell RA: CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 1998;16: 111–135.
Laman JD, Claassen E, Noelle RJ: Immunodeficiency due to a faulty interaction between T cells and B cells. Curr Opin Immunol 1994; 6:636–641.
van Kooten C, Banchereau J: CD40-CD40 ligand. J Leukoc Biol 2000;67:2–17.
Notarangelo LD, Hayward AR: X-linked immunodeficiency with hyper-IgM (XHIM). Clin Exp Immunol 2000;120:399–405.
Vyse TJ, Kotzin BL: Genetic basis of systemic lupus erythematosus. Curr Opin Immunol 1996;8: 843–851.
Datta SK, Kalled SL: CD40-CD40 ligand interaction in autoimmune disease. Arthritis Rheum 1997; 40:1735–1745.
Daikh DI, Finck BK, Linsley, PS, Hollenbaugh D, Wofsy D: Longterm inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J Immunol 1997;159:3104–3108.
Kalled SL, Cutler AH, Datta SK, Thomas DW: Anti-CD40 ligand antibody treatment of SNFI mice with established nephritis: preservation of kidney function. J Immunol 1998;160:2158–2165.
Higuchi T, Aiba Y, Nomura T, Matsuda J, Mochida K, Suzuki M, et al.: Cutting Edge: Ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune disease. J Immunol 2002;168: 9–12.
Santos-Argumedo L, Alvarez-Maya I, Romero-Ramirez H, Flores-Romo L: Enforcedand prolonged CD40 ligand expression triggers autoantibody production in vivo. Eur J Immunol 2001;31:3484–3492.
Yellin MJ, D'Agati V, Parkinson G, Han AS, Szema A, Baum D, et al.: Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides. Arthritis Rheum 1997;40:124–134.
Harigai M, Hara M, Fukasawa C, Nakazawa S, Kawaguchi Y, Kamatani N, Kashiwazaki S: Responsiveness of peripheral blood B cells to recombinant CD40 ligand in patients with systemic lupusery thematosus. Lupus 1999; 8:227–233.
Koshy M, Berger D, Crow MK: Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 1996;98:826–837.
Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK: Hyperex-pression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 1996;97: 2063–2073.
Devi BS, Van Noordin S, Krausz T, Davies KA: Peripheral blood lymphocytes in SLE—hyperexpression of CD154 on T and B lymphocytes and increased number of double negative T cells. J Autoimmun 1998;11:471–475.
Cron RQ, Genin, A, Brunner M: Regulation of CD154 in systemic lupus erythematosus (abstract). Ann Rheum Dis 2001; 60:82.
Mishra N, Brown DR, Olorenshaw IM, Kammer GM: Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-gamma gene and protein expression in lupus T cells. Proc Natl Acad Sci USA 2001;98: 2628–2633.
Vakkalanka RK, Woo C, Kirou KA, Koshy M, Berger D, Crow MK: Elevated levels and functional capacity of soluble CD40 ligand in systemic lupus erythematosus sera. Arthritis Rheum 1999;42: 871–881.
Kato K, Santana-Sahagun E, Rassenti LZ, Weisman MH, Tamura N, Kobayashi S, Hashimoto H, Kipps TJ: The soluble CD40 ligands CD154 in systemic lupus erythematosus. J Clin Invest 1999;104:947–955.
Ludewig B, Henn V, Schroder JM, Graf D, Kroczek RA: Induction, regulation, and function of soluble TRAP (CD40 ligand) during interaction of primary CD4+ CD45RA+ T cells with dendritic cells. Eur J Immunol 1996;26: 3137–3143.
Scalzi LV, Cron RQ, Vonfeldt JM. Correlatino of increased soluble CD40 ligand levels and coronary artery calcification in SLE patients (abstract). Arthritis Rheum 2002; 45 (suppl 9):S55.
MacDonald KP, Nishioka Y, Lipsky PE, Thomas R: Functional CD40 ligand isexpressed by T cells in rheumatoid arthritis. J Clin Invest 1997;100:2404–2414.
Berner B, Wolf G, Hummel KM, Muller GA, Reuss-Borst MA: Increased expression of CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis. Ann Rheum Dis 2000;59:190–195.
Tamura N, Kobayashi S, Kato K, Bando H, Haruta K, Oyanagi M, et al.: Soluble CD154 in rheumatoid arthritis: elevated plasma levels in cases with vasculitis. J Rheumatol 2001;28:2583–2590.
Valentini G, Romano MF, Naclerio C, Bisogni R, Lamberti A, Turco MC, Venuta S: Increased expression of CD40 ligand in activated CD4+ T lymphocytes of systemisclerosis patients. J Autoimmun 2000;15:61–66.
Battaglia E, Biancone L, Resegotti A, Emanuelli G, Fronda GR, Camussi G: Expression of CD40 and its ligand, CD40L, in intestinal lesions of Crohn's disease. Am J Gastroenterol 1999;94: 3279–3284.
Liu Z, Colpaert S, D'Haens GR, Kasran A, de Boer M, Rutgeerts P, et al.: Hyper expression of CD40 ligand (CD154) in inflammatory bowel disease and its contribution to pathogenic cytokine production. J Immunol 1999;163:4049–4057.
Webber NP, Mascarenhas JO, Crow MK, Bussel J, Schattner EJ: Functional properties of lymphocytes in idiopathic thrombocy-topenic purpura. Hum Immunol 2001;62:1346–1355.
Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, et al.: Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 1999;286:2352–2355.
Schonbeck U, Mach F, Sukhova GK, Atkinson E, Levesque E, Herman M, et al.: Expression of stromelysin-3 in atherosclerotic lesions: regulation via CD40-CD40 ligand signaling in vitro and in vivo. J Exp Med 1999;189: 843–853.
Lutgens E, Gorelik L, Daemen MJ, de Muinck ED, Grewal IS, Koteliansky VE, Flavell RA: Requirement for CD154 in the progression of atherosclerosis. Nat Med 1999;5:1313–1316.
Mach F, Schonbeck U, Sukhova GK, Bourcier T, Bonnefoy JY, Pober JS, Libby P: Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA 1997;94:1931–1936.
Aukrust P, Muller F, Ueland T, Berget T, Aaser E, Brunsvig A, et al.: Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999;100: 614–620.
Wierda WG, Kipps TJ: Gene therapy of hematologic malignancies. Semin Oncol 2000;27:502–511.
Sun Y, Peng D, Lecanda J, Schmitz V, Barajas M, Qian C, Prieto J: In vivo gene transfer of CD40 ligand into colon cancer cells induces local production of cytokines and chemokines, tumor eradication and protective antitumor immunity. Gene Ther 2000;7:1467–1476.
Sacco MG, Ungari M, Cato EM, Villa A, Strina D, Notarangelo LD, et al.: Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome. Cancer Gene Ther 2000;7:1299–1306.
Brown MP, Topham DJ, Sangster MY, Zhao J, Flynn KJ, Surman SL, et al.: Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. Nat Med 1998;4: 1253–1260.
Wolthers KC, Otto SA, Lens SM, Van Lier RA, Miedema F, Meyaard L: Functional B cell abnormalities in HIV type I infection: role of CD40L and CD70. AIDS Res Hum Retroviruses 1997;13:1023–1029.
Davis JC, Jr., Totoritis MC, Rosenberg J, Sklenar TA, Wofsy D: Phase 1 clinicaltrial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 2001;28:95–101.
Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB: Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000;6:114.
Nonoyama S, Penix LA, Edwards CP, Lewis DB, Ito S, Aruffo A, et al.: Diminished expression of CD40 ligand by activated neonatal T cells. J Clin Invest 1995; 95:66–75.
Skov S, Bonyhadi M, Odum N, Ledbetter JA: IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells. J Immunol 2000;164:3500–3505.
Gray JD, Liu T, Huynh N, Horwitz DA: Transforming growth factor beta enhances the expression of CD154 (CD40L) and production of tumor necrosis factor alpha by human T lymphocytes. Immunol Lett 2001;78:83–88.
Fuleihan R, Ramesh N, Horner A, Ahern D, Belshaw PJ, Alberg DG, et al.: Cyclosporin A inhibits CD40 ligand expression in T lymphocytes. J Clin Invest 1994;93: 1315–1320.
Ho S, Clipstone N, Timmermann L, Northrop J, Graef I, Fiorentino D, Nourse J, Crabtree GR: The mechanism of action of cyclosporin A and FK 506. Clin Immunol Immunopathol 1996;80:S40-S45.
Crabtree GR: Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT. Cell 1999;96:611–614.
Rao A, Luo C, Hogan PG: Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 1997;15: 707–747.
Brorson KA, Beverly B, Kang SM, Lenardo M, Schwartz RH: Transcriptional regulation of cytokine genes in nontransformed T cells. Apparent constitutive signals in run-on assays can be caused by repeat sequences. J Immunol 1991;147:3601–3609.
Pilia G, Porta G, Padayachee M, Malcolm S, Zucchi I, Villa A, et al.: Human CD40L gene maps between DXS144E and DXS300 in Xq26. Genomics 1994;22:249–251.
Villa A, Notarangelo LD, Di Santo JP, Macchi PP, Strina D, Frattini A, et al.: Organization of the human CD40L gene: implications for molecular defects in X chromosome-linked hyper-IgM syndrome and prenatal diagnosis. Proc Natl Acad Sci USA 1994;91:2110–2114.
Cron RQ, Schubert LA, Lewis DB, Hughes CC: Consistent transient transfection of DNA into non-transformed human and murne T-lymphocytes. J Immunol Methods 1997;205:145–150.
Schubert LA, King G, Cron RQ, Lewis DB, Aruffo A, Hollenbaugh D: The human gp39 promoter. Two distinct nuclear factors of activated T cell protein-binding elements contribute independently to transcriptional activation. J Biol Chem 1995;270:29,624–29,627.
Lobo FM, Xu S, Lee C, Fuleihan RL. Transcriptional Activity of the Distal CD40 Ligand Promoter. Biochem Biophys Res Commun 2000;279:245–250.
Tsytsykova AV, Tsitsikov EN, Geha RS: The CD40L promoter contains nuclear factor of activated T cells-binding motifs which require AP-1 binding for activation of transcription. J Biol Chem 1996; 271:3763–3770.
Parra E, Mustelin T, Dohlsten M, Mercola D: Identification of a CD28 Response Element in the CD40 Ligand Promoter. J Immunol 2001;166:2437–2443.
Lobo FM, Zanjani R, Ho N, Chatila TA, Fuleihan RL: Calcium-dependent activation of TNF family gene expression by Ca2+/calmodulin kinase type IV/Gr and calcineurin. J Immunol 1999;162: 2057–2063.
Ishikawa S, Akakura S, Abe M, Terashima K, Chijiiwa K, Nishimura H, et al.: A subset of CD4+ T cells expressing early activation antigen CD69 in murine lupus: possible abnormal regulatory role for cytokine imbalance. J Immunol 1998;161:1267–1273.
Santana MA, Pedraza-Alva G, Olivares-Zavaleta N, Madrid-Marina V, Horejsi V, Burakoff SJ, Rosenstein Y: CD43-mediated signals induce DNA binding activity of AP-1, NF-AT, and NFkappa B transcription factors in human T lymphocytes. J Biol Chem 2000; 275:31,460–31,468.
Siddiqa A, Sims-Mourtada JC, Guzman-Rojas L, Rangel R, Guret C, Madrid-Marina V, et al.: Regulation of CD40 and CD40 ligand by the AT-book transcription factor AKNA. Nature 2001;410: 383–387.
Srahna M, Remacle JE, Annamulai K, Pype S, Huylebroeck D, Boogaerts MA, Vandenberghe P; NF-kappa B is involved in the regulation of CD154 (CD40 ligand) expression in primary human T cells. Clin Exp Immunol 2001; 125:229–236.
Lindgren H, Axcrona K, Leanderson T: Regulation of transcriptional activity of the murine CD40 ligand promoter in response to signals through TCR and the costimulatory molecules CD28 and CD2. J Immunol 2001;166:4578–4585.
Crow MK, Kirou KA: Regulation of CD40 ligand expression in systemic lupusery thematos us. Curr Opin Rheumatol 2001;13:361–369.
Li-Weber M, Laur O, Krammer PH: Novel Egr/NF-AT composite sites mediate activation of the CD95 (APO- 1/Fas) ligand promoter in response to T cell stimulation. Eur J Immunol 1999;29:3017–3027.
Mittelstadt PR, Ashwell JD: Cyclosporin A-sensitive transcription factor Egr-3 regulates Fas ligand expression. Mol Cell Biol 1998;18:3744–3751.
Aringer M, Stummvoll GH, Steiner G, Koller M, Steiner CW, Hofler E, et al. Serum interleukin-15 is elevated in systemic lupus erythematosus. Rheumatology (Oxford) 2001;40:876–881.
Rigby WF, Waugh MG, Hamilton BJ: Characterization of RNA binding proteins associated with CD40 ligand (CD154) mRNA turnover in human T lymphocytes. J Immunol 1999;163:4199–4206.
Ford GS, Barnhart B, Shone S, Covey LR: Regulation of CD154 (CD40 ligand) mRNA stability during T cell activation. J Immunol 1999;162:4037–4044.
Barnhart B, Kosinski PA, Wang Z, Ford GS, Kiledjian M, Covey LR: Identification of a complex that binds to the CD154 3′ untranslated region: implications for a role in message stability during T cell activation. J Immunol 2000;165: 4478–4486.
Hamilton BJ, Genin A, Cron RQ, Rigby WFC: Delineation of a novel pathway that regulates CD154 (CD40 ligand) expression. Mol Cell Biol 2003; in press.
Casamayor-Palleja M, Khan M, MacLennan IC: A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex. J Exp Med 1995;181:1293–1301.
Suarez A, Mozo L, Gayo A, Zamorano J, Gutierrez C: REquirement of a second signal via protein kinase C or protein kinase A for maximal expression of CD40 ligand. Involvement of transcriptional and post transcriptional mechanisms. Eur J Immunol 1997;27:2822–2829.
Schubert LA, Cron RQ, Cleary AM, Brumer M, Song A, Lu L-S, et al.: A T cell-specific enhancer of the human CD40 ligand gene. J Biol Chem 2002;277:7386–7395.
Kuprash DV, Udalova IA, Turetskaya RL, Rice NR, Nedospasov SA: Conserved kappa B element located downstream of the tumor necrosis factor alphagene: distinct NF-kappa B binding pattern and enhancer activity in LPS activated murine macrophages. Oncogene 1995;11:97–106.
Trede NS, Tsytsykova AV, Chatila T, Goldfeld AE, Geha RS: Transcriptional activation of the human TNF-alpha promoter by super-antigen in human monocytic cells: role of NF-kappa B. J Immunol 1995;155:902–908.
Seyama K, Kira S, Ishidoh K, Souma S, Miyakawa T, Kominami E: Genomic structure and PCR-SSCP analysis of the human CD40 ligand gene: its application to prenatal screening for X-linked hyper-IgM syndrome. Hum Genet 1996; 97:180–185.
Blackwood EM, Kadonaga JT: Going the distance: a current view of enhancer action. Science 1998;281:61–63.
Shapiro VS, Mollenauer MN, Weiss A: Nuclear factor of activated T cells and AP-1 are insufficient for IL-2 promoter activation: requirement for CD28 up-regulation of RE/AP. J Immunol 1998;161: 6455–6458.
Shapiro VS, Mollenauer MN, Greene WC, Weiss A: c-rel regulation of IL-2 gene expression may be mediated through activation of AP-1. J Exp Med 1996;184: 1663–1669.
Wong HK, Kammer GM, Dennis G, Tsokos GC: Abnormal NF-kappa B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression. J Immunol 1999;163: 1682–1689.
Fujita T, Nolan GP, Ghosh S, Baltimore D: Independent modes of transcriptional activation by the p50 and p65 subunits of NF-kappa B. Genes Dev 1992;6: 775–787.
Lin R, Gewert D, Hiscott J: Differential transcriptional activation in vitro by NF-kappa B/Rel proteins. J Biol Chem 1995;270: 3123–3131.
Cockerill PN: Identification of DNasel hypersensitive sites within nuclei. Methods Mol Biol 2000;130:29–46.
Shimadzu M, Nunoi H, Terasaki H, Ninomiya R, Iwata M, Kanegasaka S, Matsuda I. Structural organization of the gene for CD40 ligand: molecular analysis for diagnosis of X-linked hyper-IgM syndrome. Biochim Biophys Acta 1995;1260:67–72.
Cron RQ, Ezquerra A, Coligan JE, Houlden BA, Blvestone JA, Maloy WL: Identification of distinct T cell receptor (TCR)-gamma delta heterodimers using an anti-TCR-gamma variable region serum. J Immunol 1989;143:3769–75.
Yellin MJ, Lee JJ, Chess L, Lederman S: A human CD4- T cell leukemia subclone with contact-dependent helper function. J Immunol 1991;147:3389–3395.
Agarwal S, Avni O, Rao A: Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity 2000;12:643–652.
Cron RQ, Genin A, Brunner M: Identification of a novel GATA-regulated CD154 transcriptional enhancer (abstract). Faseb J 2002; 16:A694.
Garcia-Rodriguez C, Rao A: Nuclear factor of activated T cells (NFAT)-dependent transactivation regulated by the coactivators p300/CREB-binding protein (CBP). J Exp Med 1998;187:12031–2036.
Ouyang W, Lohning M, Gao Z, Assenmacher M, Ranganath S, Radbruch A, Murphy KM: Atat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 2000;12:27–37.
Lee HJ, Takemoto N, Kurata H, Kamogawa Y, Miyatake S, O'Garra A, Arai N: GATA-3 induces Thelper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Thl cells. J Exp Med 2000;192:105–115.
Miaw SC, Choi A, Yu E, Kishikawa H, Ho IC: ROG, repressor of GATA, regulates the expression of cytokine genes. Immunity 2000; 12:323–333.
Smith VM, Lee PP, Szychowski S, Winoto A: GATA-3 dominant negative mutant. Functional redundancy of the T cell receptor alpha and beta enhancers. J Biol Chem 1995;270:1515–1520.
Hural JA, Kwan M, Henkel G, Hock MB, Brown MA: An intron transcriptional enhancer element regulates IL-4 gene locus accessibility in mast cells. J Immunol 2000;165:3239–3249.
Ciccarone VC, Chrivia J, Hardy KJ, Young HA: Identification of enhancer-like elements in human IFN-gamma genomic DNA. J Immunol 1990;144:725–730.
Takemoto N, Kamogawa Y, Jun Lee H, Kurata H, Arai K, O'Garra A, et al.: Cutting edge: chromatin remodeling at the IL-4/IL-13 intergenic regulatory region for Th2-specific cytokine gene cluster. J Immunol 2000;165: 6687–6691.
Barry SC, Seppen J, Ramesh N, Foster JL, Seyama K, Ochs HD, et al.: Lentiviral and murine retroviral transduction of T cells for expression of human CD40 ligand. Hum Gene Ther 2000;11: 323–332.
Grohmann U, Fallarino F, Silla S, Bianchi R, Belladonna ML, Vacca C, et al.: CD40 ligation ablates the tolerogenic potential of lymphoid dendritic cells. J Immunol 2001; 166:277–283.
Hong JC, Kahan BD: Immunosuppressive agents in organ transplantation: past, present, and future. Semin Nephrol 2000;20: 108–125.
Mackey MF, Gunn JR, Ting PP, Kikutani H, Dranoff G, Noelle RJ, Barth RJ Jr: Protective immunity induced by tumor vaccines requires interaction between CD40 and its ligand, CD154. Cancer Res 1997; 57:2569–2574.
Nakajima A, Kodama T, Morimoto S, Azuma M, Takeda K, Oshima H, et al.: Antitumor effect of CD40 ligand: elicitation of local and systemic antitumor responses by IL-12 and B7. J Immunol 1998; 161:1901–1907.
Arpin C, Dechanet J, Van Kooten C, Merville P, Grouard G, Briere F, et al.: Generation of memory B cells and plasma cells in vitro. Science 1995:268:720–722.
Liu YJ, Malisan F, de Bouteiller O, Guret C, Lebecque S, Banchereau J, et al.: Within germinal centers, isotypes witching of immunoglobul in genes occurs after the onset of somatic mutation. Immunity 1996;4:241–250.
Randall TD, Heath AW, Santos-Argumedo L, Howard MC, Weissman IL, Lund FE: Arrest of B lymphocyte terminal differentiation by CD40 signaling: mechanism for lack of antibody-secreting cells in germinal centers. Immunity 1998;8:733–742.
Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G: Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 1996;184:747–752.
Kiener PA, Moran-Davis P, Rankin BM, Wahl AF, Aruffo A, Hollenbaugh D: Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J Immunol 1995;155:4917–4925.
Ridge JP, Di Rosa F, Matzinger P: A conditioned dendritic cell can be atemporal bridge between a CD4+ T-helperanda T-killer cell. Nature 1998;393:474–478.
Blotta MH, Marshall JD, DeKruyff RH, Umetsu DT: Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a costimulatory signal that up-regulates IL-4 synthesis. J Immunol 1996; 156:3133–3140.
Perez-Melgosa M, Hollenbaugh D, Wilson CB: Cutting edge: CD40 ligand is a limiting factor in the humoral response to T cell-dependent antigens. J Immunol 1999;163:1123–1127.
Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P: Reduction of atheros clerosis in mice by inhibition of CD40 signalling. Nature 1998;394:200–203.
Buning C, Kruger K, Sieber T, Schoeler D, Schriever F: Increased expression of CD40 ligand on activated T cells of patients with colon cancer. Clin Cancer Res 2002;8: 1147–1151.
Durie FH, Aruffo A, Ledbetter J, Crassi KM, Green WR, Fast LD, Noelle RJ: Antibody to the ligand of CD40, gp39, blocks the occrence of the acute and chronic forms of graft-vs-host disease. J Clin Invest 1994;94: 1333–1338.
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). J Exp Med 1992;175:1091–1101.
Cron RQ: HIV-1, NFAT, and cyclosporin: immunosuppression for the immunosuppressed? DNA Cell Biol 2001;20:761–767.
Cron RQ, Bort SJ, Wang Y, Brunvand MW, Lewis DB: T cell priming enhances IL-4 gene expression by increasing nuclear factor of activated T cells. J Immunol 1999; 162:860–870.
Cron RQ, Bartz SR, Clausell A, Bort SJ, Klebanoff SJ, Lewis DB: NFATI enhances HIV-1 gene expression in primary human CD4 T cells. Clin Immunol 2000;94:179–191.
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Cron, R.Q. CD154 transcriptional regulation in primary human CD4 T cells. Immunol Res 27, 185–202 (2003). https://doi.org/10.1385/IR:27:2-3:185
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DOI: https://doi.org/10.1385/IR:27:2-3:185