CD40 (protein)
CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.
Deficiency can cause Hyper-IgM syndrome type 3.
Function
The protein receptor encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The TNFR-receptor associated factor adaptor proteins TRAF1, TRAF2, TRAF6 and possibly TRAF5 interact with this receptor and serve as mediators of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.[1]
Specific effects on cells
In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L (CD154) 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 increase in activation results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbe.
The B cell can present antigens to helper T cells. If the T cell recognizes the peptide presented by the B cell, the T cell synthesizes CD40L. The CD40L binds to the B cell's CD40 receptor which causes resting B cell activation. The T cell also produces IL-4 which directly binds to B cell receptors. As a result of this interaction, the B cell can undergo division, antibody isotype switching, and differentiation to plasma cells. The end result is a B cell which is able to mass produce specific antibodies against an antigenic target.
The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including dendritic cells, B cells and macrophages. It can also be expressed by endothelial cells, smooth muscle cells, fibroblasts and epithelial cells. Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell haematopoiesis (10)
Interactions
CD40 (protein) has been shown to interact with TRAF2,[2][3][4] TRAF3,[3][5][6][7] TRAF6,[3][7] TRAF5[3][8] and TTRAP.[9]
References
- ^ "Entrez Gene: CD40 CD40 molecule, TNF receptor superfamily member 5". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=958.
- ^ McWhirter, S M; Pullen S S, Holton J M, Crute J J, Kehry M R, Alber T (Jul. 1999). "Crystallographic analysis of CD40 recognition and signaling by human TRAF2". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 96 (15): 8408–13. doi:10.1073/pnas.96.15.8408. ISSN 0027-8424. PMC 17529. PMID 10411888. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=17529.
- ^ a b c d Tsukamoto, N; Kobayashi N, Azuma S, Yamamoto T, Inoue J (Feb. 1999). "Two differently regulated nuclear factor κB activation pathways triggered by the cytoplasmic tail of CD40". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 96 (4): 1234–9. doi:10.1073/pnas.96.4.1234. ISSN 0027-8424. PMC 15446. PMID 9990007. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=15446.
- ^ Malinin, N L; Boldin M P, Kovalenko A V, Wallach D (Feb. 1997). "MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1". Nature (ENGLAND) 385 (6616): 540–4. doi:10.1038/385540a0. ISSN 0028-0836. PMID 9020361.
- ^ Hu, H M; O'Rourke K, Boguski M S, Dixit V M (Dec. 1994). "A novel RING finger protein interacts with the cytoplasmic domain of CD40". J. Biol. Chem. (UNITED STATES) 269 (48): 30069–72. ISSN 0021-9258. PMID 7527023.
- ^ Ni, C Z; Welsh K, Leo E, Chiou C K, Wu H, Reed J C, Ely K R (Sep. 2000). "Molecular basis for CD40 signaling mediated by TRAF3". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 97 (19): 10395–9. doi:10.1073/pnas.97.19.10395. ISSN 0027-8424. PMC 27035. PMID 10984535. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=27035.
- ^ a b Roy, N; Deveraux Q L, Takahashi R, Salvesen G S, Reed J C (Dec. 1997). "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. (ENGLAND) 16 (23): 6914–25. doi:10.1093/emboj/16.23.6914. ISSN 0261-4189. PMC 1170295. PMID 9384571. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1170295.
- ^ Ishida, T K; Tojo T, Aoki T, Kobayashi N, Ohishi T, Watanabe T, Yamamoto T, Inoue J (Sep. 1996). "TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 93 (18): 9437–42. doi:10.1073/pnas.93.18.9437. ISSN 0027-8424. PMC 38446. PMID 8790348. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=38446.
- ^ Pype, S; Declercq W, Ibrahimi A, Michiels C, Van Rietschoten J G, Dewulf N, de Boer M, Vandenabeele P, Huylebroeck D, Remacle J E (Jun. 2000). "TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation". J. Biol. Chem. (UNITED STATES) 275 (24): 18586–93. doi:10.1074/jbc.M000531200. ISSN 0021-9258. PMID 10764746.
- Carlring, Jennifer; AlTaher HM, Clark S, Chen X, Latimer SL, Jenner T, Buckle AM, Heath AW (2011). "CD154-CD40 interactions in the control of B cell hematopoiesis". J.Leuk Biol 89 (5): 697–706. doi:10.1189/jlb.0310179.
Further reading
- Parham, Peter (2004). The Immune System (2nd ed.). Garland Science. pp. 169–173. ISBN 0-8153-4093-1.
- Coico R, Sunshine G, and Benjamin E (2003). Immunology: A Short Course. p. 97.
- Clark EA (1991). "CD40: a cytokine receptor in search of a ligand". Tissue Antigens 36 (1): 33–6. doi:10.1111/j.1399-0039.1990.tb01795.x. PMID 1701063.
- Banchereau J, Bazan F, Blanchard D et al. (1994). "The CD40 antigen and its ligand". Annu. Rev. Immunol. 12: 881–922. doi:10.1146/annurev.iy.12.040194.004313. PMID 7516669.
- van Kooten C, Banchereau J (2000). "CD40-CD40 ligand". J. Leukoc. Biol. 67 (1): 2–17. PMID 10647992.
- Schattner EJ (2003). "CD40 ligand in CLL pathogenesis and therapy". Leuk. Lymphoma 37 (5–6): 461–72. doi:10.3109/10428190009058499. PMID 11042507.
- Bhushan A, Covey LR (2002). "CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes". Immunol. Res. 24 (3): 311–24. doi:10.1385/IR:24:3:311. PMID 11817328.
- Cheng G, Schoenberger SP (2002). "CD40 signaling and autoimmunity". Curr. Dir. Autoimmun.. Current Directions in Autoimmunity 5: 51–61. doi:10.1159/000060547. ISBN 3-8055-7308-1. PMID 11826760.
- Dallman C, Johnson PW, Packham G (2003). "Differential regulation of cell survival by CD40". Apoptosis 8 (1): 45–53. doi:10.1023/A:1021696902187. PMID 12510151.
- O'Sullivan B, Thomas R (2004). "Recent advances on the role of CD40 and dendritic cells in immunity and tolerance". Curr. Opin. Hematol. 10 (4): 272–8. doi:10.1097/00062752-200307000-00004. PMID 12799532.
- Benveniste EN, Nguyen VT, Wesemann DR (2004). "Molecular regulation of CD40 gene expression in macrophages and microglia". Brain Behav. Immun. 18 (1): 7–12. doi:10.1016/j.bbi.2003.09.001. PMID 14651941.
- Xu Y, Song G (2005). "The role of CD40-CD154 interaction in cell immunoregulation". J. Biomed. Sci. 11 (4): 426–38. doi:10.1159/000077892. PMID 15153777.
- Contin C, Couzi L, Moreau JF et al. (2004). "[Immune dysfuntion of uremic patients: potential role for the soluble form of CD40]". Néphrologie 25 (4): 119–26. PMID 15291139.
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| 1-50 |
CD1 ( a-c, 1A, 1D, 1E) · CD2 · CD3 ( γ, δ, ε) · CD4 · CD5 · CD6 · CD7 · CD8 ( a) · CD9 · CD10 · CD11 ( a, b, c) · CD13 · CD14 · CD15 · CD16 ( A, B) · CD18 · CD19 · CD20 · CD21 · CD22 · CD23 · CD24 · CD25 · CD26 · CD27 · CD28 · CD29 · CD30 · CD31 · CD32 ( A, B) · CD33 · CD34 · CD35 · CD36 · CD37 · CD38 · CD39 · CD40 · CD41 · CD42 ( a, b, c, d) · CD43 · CD44 · CD45 · CD46 · CD47 · CD48 · CD49 ( a, b, c, d, e, f) · CD50
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| 51-100 |
CD51 · CD52 · CD53 · CD54 · CD55 · CD56 · CD57 · CD58 · CD59 · CD61 · CD62 ( E, L, P) · CD63 · CD64 ( A, B, C) · CD66 ( a, b, c, d, e, f) · CD68 · CD69 · CD70 · CD71 · CD72 · CD73 · CD74 · CD78 · CD79 ( a, b) · CD80 · CD81 · CD82 · CD83 · CD84 · CD85 ( a, d, e, h, j, k) · CD86 · CD87 · CD88 · CD89 · CD90 · CD91- CD92 · CD93 · CD94 · CD95 · CD96 · CD97 · CD98 · CD99 · CD100
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| 101-150 |
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| 151-200 |
CD151 · CD152 · CD153 · CD154 · CD155 · CD156 ( a, b, c) · CD157 · CD158 ( a, d, e, i, k) · CD159 ( a, c) · CD160 · CD161 · CD162 · CD163 · CD164 · CD166 · CD167 ( a, b) · CD168 · CD169 · CD170 · CD171 · CD172 ( a, b, g) · CD174 · CD177 · CD178 · CD179 ( a, b) · CD181 · CD182 · CD183 · CD184 · CD185 · CD186 · CD191 · CD192 · CD193 · CD194 · CD195 · CD196 · CD197 · CDw198 · CDw199 · CD200
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| 201-250 |
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| 251-300 |
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| 301-350 |
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| Lymphoid |
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| Myeloid |
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| Stem cell |
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cell/phys (coag, heme, immu, gran), csfs
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rbmg/mogr/tumr/hist, sysi/epon, btst
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drug (B1/2/3+5+6), btst, trns
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cell/phys/auag/auab/comp, igrc
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Chemokine receptor
(GPCRs) |
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| TNF receptor |
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| JAK-STAT |
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| Ig superfamily |
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| IL-17 family |
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| S/T |
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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