CD38: An Ecto-Enzyme at the Crossroads of Innate and Adaptive Immune Responses

  • Santiago Partidá-Sánchez
  • Laura Rivero-Nava
  • Guixiu Shi
  • Frances E. Lund
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 590)


No one would dispute that intracellular enzymes such as kinases and phosphatases play critical roles in regulating the development, activation, differentiation, and survival of lymphocytes1. However, it is less well appreciated that cells of the immune system also express many membrane-associated ecto-enzymes that have the potential to regulate immune cell function. Ecto-enzymes have their active sites located on the outside of the cell and therefore must utilize substrates that are found in the extracellular milieu. Some of these enzymes, such as CD26, act as peptidases, while others, including CD73, CD38, CD39, ART2, and PC-1, utilize nucleotides as substrates. Although it was proposed that these nucleotide-utilizing enzymes might be involved in salvaging purines2 or in generating products such as ATP, ADP, and adenosine that function as signaling molecules for purinergic receptors3, until recently very little was known about the functional roles these enzymes might play during immune responses. However, in the last 10 years it has become clear that many of these enzymes play very important roles in regulating the survival, activation, and effector function of leukocytes4. Our laboratory has spent the last several years assessing the role of one of these ectoenzymes, CD38, in immune responses. In this article, we will review our recent work, focusing on the role that CD38 plays in regulating innate and adaptive immune responses.


Adaptive Immune Response Calcium Response CCR7 Ligand CD38KO Mouse Ovum Peptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

6. References

  1. 1.
    J.L. Cannons and P.L. Schwartzberg. Fine-tuning lymphocyte regulation: what’s new with tyrosine kinases and phosphatases? Curr Opin Immunol 16:296–303 (2004).PubMedCrossRefGoogle Scholar
  2. 2.
    P. Deterre, L. Gelman, H. Gary-Gouy, C. Arrieumerlou, V. Berthelier, J.-M. Tixier, S. Ktorza, J. Goding, C. Schmitt and G. Bismuth. Coordinated regulation in human T cells of nucleotide-hydrolyzing ecto-enzymatic activities, including CD38 and PC-1. J Immunol 157:1381–1388 (1996).PubMedGoogle Scholar
  3. 3.
    R. Resta, Y. Yamashita and L.F. Thompson. Ecto-enzyme and signaling functions of lymphocyte CD73. Immunol Rev 161:95–109 (1998).PubMedCrossRefGoogle Scholar
  4. 4.
    M. Salmi and S. Jalkanen. Cell-surface enzymes in control of leukocyte trafficking. Nat Rev Immunol 5:760–771 (2005).PubMedCrossRefGoogle Scholar
  5. 5.
    F. Schuber and F.E. Lund. Structure and enzymology of ADP-ribosyl cyclases: conserved enzymes that produce multiple calcium mobilizing metabolites. Curr Mol Med 4:249–261 (2004).PubMedCrossRefGoogle Scholar
  6. 6.
    H.C. Lee and R. Aarhus. ADP-ribosyl cyclase: an enzyme that cyclizes NAD+ into a calcium mobilizing metabolite. Cell Regul 2:203–209 (1991).PubMedGoogle Scholar
  7. 7.
    M.R. Hellmich and F. Strumwasser. Purification and characterization of a molluscan egg-specific NADase, a second-messenger enzyme. Cell Regul 2:193–202 (1991).PubMedGoogle Scholar
  8. 8.
    S.P. Goodrich, H. Muller-Steffner, A. Osman, M.J. Moutin, K. Kusser, A. Roberts, D.L. Woodland, T.D. Randall, E. Kellenberger, P.T. LoVerde, F. Schuber and F.E. Lund. Production of calcium-mobilizing metabolites by a novel member of the ADP-ribosyl cyclase family expressed in Schistosoma mansoni. Biochemistry 44:11082–11097 (2005).PubMedCrossRefGoogle Scholar
  9. 9.
    D.G. Jackson and J.I. Bell. Isolation of a cDNA encoding the human CD38 (T10) molecule, a cell surface glycoprotein with an unusual discontinuous pattern of expression during lymphocyte differentiation. J Immunol 144:2811–2815 (1990).PubMedGoogle Scholar
  10. 10.
    H.C. Lee. Multiplicity of Ca2+ messengers and Ca2+ stores: a perspective from cyclic ADP-ribose and NAADP. Curr Mol Med 4:227–237 (2004).PubMedCrossRefGoogle Scholar
  11. 11.
    F.J. Kuhn, I. Heiner and A. Luckhoff. TRPM2: a calcium influx pathway regulated by oxidative stress and the novel second messenger ADP-ribose. Pflugers Arch 451:212–219 (2005).PubMedCrossRefGoogle Scholar
  12. 12.
    A.H. Guse. Regulation of calcium signaling by the second messenger cyclic adenosine diphosphoribose (cADPR). Curr Mol Med 4:239–248 (2004).PubMedCrossRefGoogle Scholar
  13. 13.
    J.E. Fernandez, S. Deaglio, D. Donati, I.S. Beusan, F. Corno, A. Aranega, M. Forni, B. Falini and F. Malavasi. Analysis of the distribution of human CD38 and of its ligand CD31 in normal tissues. J Biol Reg Homeost Agents 12:81–91 (1998).Google Scholar
  14. 14.
    F. Malavasi, A. Funaro, M. Alessio, L.B. De Monte, C.M. Ausiello, U. Dianzani, F. Lanza, E. Magrini, M. Momo and S. Roggero. CD38: a multi-lineage cell activation molecule with a split personality. Int J Clin Lab Res 22:73–80 (1992).PubMedCrossRefGoogle Scholar
  15. 15.
    T. Musso, S. Deaglio, L. Franco, L. Calosso, R. Badolato, G. Garbarino, U. Dianzani and F. Malavasi. CD38 expression and functional activities are up-regulated by IFN-g on human monocytes and monocytic cell lines. J Leukoc Biol 69:605–612 (2001).PubMedGoogle Scholar
  16. 16.
    B. Bauvois, L. Durant, J. Laboureau, E. Barthelemy, D. Rouillard, G. Boulla and P. Deterre. Upregulation of CD38 gene expression in leukemic B cells by interferon types I and II. J Interferon Cytokine Res 19:1059–1066 (1999).PubMedCrossRefGoogle Scholar
  17. 17.
    D. Cockayne, T. Muchamuel, J.C. Grimaldi, H. Muller-Steffner, T.D. Randall, F.E. Lund, R. Murray, F. Schuber and M.C. Howard. Mice deficient for the ecto-NAD+ glycohydrolase CD38 exhibit altered humoral immune responses. Blood 92:1324–1333 (1998).PubMedGoogle Scholar
  18. 18.
    F.E. Lund, D.A. Cockayne, T.D. Randall, N. Solvason, F. Schuber and M.C. Howard. CD38: A new paradigm in lymphocyte activation and signal transduction. Immunol Rev 161:79–93 (1998).PubMedCrossRefGoogle Scholar
  19. 19.
    S. Partida-Sanchez, S. Goodrich, K. Kusser, N. Oppenheimer, T.D. Randall and F.E. Lund. Regulation of dendritic cell trafficking by the ADP-ribosyl cyclase CD38: Impact on the development of humoral immunity. Immunity 20:279–291 (2004).PubMedCrossRefGoogle Scholar
  20. 20.
    S. Partida-Sanchez, T.D. Randall and F.E. Lund. Innate immunity is regulated by CD38. an ecto-enzyme with ADP-ribosyl cyclase activity. Microbes Infect 5:49–58 (2003).PubMedCrossRefGoogle Scholar
  21. 21.
    S. Partida-Sanchez, D.A. Cockayne, S. Monard, E.L. Jacobson, N. Oppenheimer, B. Garvy, K. Kusser, S. Goodrich, M. Howard, A. Harmsen, T.D. Randall and F.E. Lund. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med 7:1209–1216 (2001).PubMedCrossRefGoogle Scholar
  22. 22.
    S. Partida-Sanchez, P. Iribarren, M.E. Moreno-Garcia, J.-L. Gao, P.M. Murphy, N. Oppenheimer, J.M. Wang and F.E. Lund. Chemotaxis and calcium responses of phagocytes to formyl-peptide receptor ligands is differentially regulated by cyclic ADP-ribose. J Immunol 172:1896–1906 (2004).PubMedGoogle Scholar
  23. 23.
    G.J. Randolph, G. Sanchez-Schmitz and V. Angeli. Factors and signals that govern the migration of dendritic cells via lymphatics: recent advances. Springer Semin Immunopathol 26:273–287 (2005).PubMedCrossRefGoogle Scholar
  24. 24.
    M.D. Gunn, S. Kyuwa, C. Tam, T. Kakiuchi, A. Matsuzawa, L.T. Williams and H. Nakano. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 189:451–460 (1999).PubMedCrossRefGoogle Scholar
  25. 25.
    R. Forster, A. Schubel, D. Breitfeld, E. Kremmer, I. Renner-Muller, E. Wolf and M. Lipp. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23–33 (1999).PubMedCrossRefGoogle Scholar
  26. 26.
    M. Merad, M.G. Manz, H. Karsunky, A. Wagers, W. Peters, I. Charo, I.L. Weissman, J.G. Cyster and E.G. Engleman. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol 3:1135–1141 (2002).PubMedCrossRefGoogle Scholar
  27. 27.
    H.C. Lee. Physiological functions of cyclic ADP-ribose and NAADP as calcium messengers. Annu Rev Pharmacol Toxicol 41:317–345 (2001).PubMedCrossRefGoogle Scholar
  28. 28.
    E. Hosoi, C. Nishizaki, K.L. Gallagher, H.W. Wyre, Y. Matsuo and Y. Sei. Expression of the ryanodine receptor isoforms in immune cells. J Immunol 167:4887–4894 (2001).PubMedGoogle Scholar
  29. 29.
    H. Muller-Steffner, O. Malver, N.J. Oppenheimer and F. Schuber. Slow-binding inhibition of NAD+ glycohydrolase by arabino analogues of b-NAD+. J Biol Chem 267:9606–9611 (1992).PubMedGoogle Scholar
  30. 30.
    S. Deaglio and F. Malavasi. Human CD38: a receptor, an (ecto) enzyme, a disease marker and lots more. Mod Asp Immunobiol 2:121–125 (2002).Google Scholar
  31. 31.
    S. Deaglio, U. Dianzani, A.L. Horenstein, J.E. Fernandez, C. van Kooten, M. Bragardo, A. Funaro, G. Garbarino, F. Di Virgilio, J. Bancherau and F. Malavasi. Human CD38 ligand: a 120-kDA protein predominantly expressed on endothelial cells. J Immunol 156:727–734 (1996).PubMedGoogle Scholar
  32. 32.
    S. Deaglio, M. Morra, R. Mallone, C.M. Ausiello, E. Prager, G. Garbarino, U. Dianzani, H. Stockinger and F. Malavasi. Human CD38 (ADP-Ribosyl Cyclase) is a counter-receptor of CD31, an Ig superfamily member. J Immunol 160:395–402 (1998).PubMedGoogle Scholar
  33. 33.
    F.E. Lund, T.D. Randall and S. Partida-Sanchez. Cyclic ADP-ribose and NAADP. In Structures, metabolism and function, Vol. 1, pp. 217–240. Ed. H.C. Lee. New York: Kluwer Academic (2002).Google Scholar
  34. 34.
    H. Nishina, K. Inageda, K. Takahashi, S. Hoshino, K. Ikeda and T. Katada. Cell surface antigen CD38 identified as ecto-enzyme of NAD glycohydrolase has hyaluronate-binding activity. Biochem Biophys Res Comm 203:1318–1323 (1994).PubMedCrossRefGoogle Scholar
  35. 35.
    Q. Liu, I.A. Kriksunov, R. Graeff, C. Munshi, H.C. Lee and Q. Hao. Crystal structure of human CD38 extracellular domain. Structure (Cambridge) 13:1331–1339 (2005).CrossRefGoogle Scholar
  36. 36.
    C. Munshi, R. Aarhus, R. Graeff, T.F. Walseth, D. Levitt and H.C. Lee. Identification of the enzymatic active site of CD38 by site-directed mutagenesis. J Biol Chem 275:21566–21571 (2000).PubMedCrossRefGoogle Scholar
  37. 37.
    U.H. Kim, M.K. Kim, J.S. Kim, M.K. Han, B.H. Park and H.R. Kim. Purification and characterization of NAD glycohydrolase from rabbit erythrocytes. Arch Biochem Biophys 305:147–152 (1993).PubMedCrossRefGoogle Scholar
  38. 38.
    M. Seman, S. Adriouch, F. Haag and F. Koch-Nolte. Ecto-ADP-ribosyltransferases (ARTs): emerging actors in cell communication and signaling. Curr Med Chem 11:857–872 (2004).PubMedCrossRefGoogle Scholar
  39. 39.
    G.M. Barton and R. Medzhitov. Toll-like receptors and their ligands. Curr Top Microbiol Immunol 270:81–92 (2002).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Santiago Partidá-Sánchez
    • 1
  • Laura Rivero-Nava
    • 1
  • Guixiu Shi
    • 1
  • Frances E. Lund
    • 1
  1. 1.From the Trudeau InstituteSaranac LakeUSA

Personalised recommendations