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. 1996 Sep 1;184(3):955–961. doi: 10.1084/jem.184.3.955

Identification of a costimulatory molecule rapidly induced by CD40L as CD44H

PMCID: PMC2192764  PMID: 9064355

Abstract

The interaction between CD40 ligand and CD40 is critical for activation of T and B cells in vivo. We have recently demonstrated that this interaction rapidly induces a novel costimulatory activity distinct from B7 and independent of CD28. To study the molecular basis of the costimulatory activity, we have produced a novel monoclonal antibody, TM-1, that binds an 85-kilodalton costimulatory molecule rapidly induced by CD40L. Expression cloning reveals that TM-1 binds CD44H. CD44H expressed on Chinese hamster ovary cells has potent costimulatory activity for clonal expansion of T cells isolated from both wild-type mice and these with a targeted mutation of CD28. Thus, CD44H costimulates T cell proliferation by a CD28-independent mechanism. These results revealed that CD44H is a costimulatory molecule rapidly induced by CD40L.

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Selected References

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  1. Aruffo A., Farrington M., Hollenbaugh D., Li X., Milatovich A., Nonoyama S., Bajorath J., Grosmaire L. S., Stenkamp R., Neubauer M. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993 Jan 29;72(2):291–300. doi: 10.1016/0092-8674(93)90668-g. [DOI] [PubMed] [Google Scholar]
  2. Aruffo A., Stamenkovic I., Melnick M., Underhill C. B., Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990 Jun 29;61(7):1303–1313. doi: 10.1016/0092-8674(90)90694-a. [DOI] [PubMed] [Google Scholar]
  3. Budd R. C., Cerottini J. C., Horvath C., Bron C., Pedrazzini T., Howe R. C., MacDonald H. R. Distinction of virgin and memory T lymphocytes. Stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation. J Immunol. 1987 May 15;138(10):3120–3129. [PubMed] [Google Scholar]
  4. Buhlmann J. E., Foy T. M., Aruffo A., Crassi K. M., Ledbetter J. A., Green W. R., Xu J. C., Shultz L. D., Roopesian D., Flavell R. A. In the absence of a CD40 signal, B cells are tolerogenic. Immunity. 1995 Jun;2(6):645–653. doi: 10.1016/1074-7613(95)90009-8. [DOI] [PubMed] [Google Scholar]
  5. Cayabyab M., Phillips J. H., Lanier L. L. CD40 preferentially costimulates activation of CD4+ T lymphocytes. J Immunol. 1994 Feb 15;152(4):1523–1531. [PubMed] [Google Scholar]
  6. Clark E. A., Ledbetter J. A. How B and T cells talk to each other. Nature. 1994 Feb 3;367(6462):425–428. doi: 10.1038/367425a0. [DOI] [PubMed] [Google Scholar]
  7. DiSanto J. P., Bonnefoy J. Y., Gauchat J. F., Fischer A., de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):541–543. doi: 10.1038/361541a0. [DOI] [PubMed] [Google Scholar]
  8. Droll A., Dougherty S. T., Chiu R. K., Dirks J. F., McBride W. H., Cooper D. L., Dougherty G. J. Adhesive interactions between alternatively spliced CD44 isoforms. J Biol Chem. 1995 May 12;270(19):11567–11573. doi: 10.1074/jbc.270.19.11567. [DOI] [PubMed] [Google Scholar]
  9. Foy T. M., Laman J. D., Ledbetter J. A., Aruffo A., Claassen E., Noelle R. J. gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. J Exp Med. 1994 Jul 1;180(1):157–163. doi: 10.1084/jem.180.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fuleihan R., Ramesh N., Loh R., Jabara H., Rosen R. S., Chatila T., Fu S. M., Stamenkovic I., Geha R. S. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2170–2173. doi: 10.1073/pnas.90.6.2170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gray D., Dullforce P., Jainandunsing S. Memory B cell development but not germinal center formation is impaired by in vivo blockade of CD40-CD40 ligand interaction. J Exp Med. 1994 Jul 1;180(1):141–155. doi: 10.1084/jem.180.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Green J. M., Noel P. J., Sperling A. I., Walunas T. L., Gray G. S., Bluestone J. A., Thompson C. B. Absence of B7-dependent responses in CD28-deficient mice. Immunity. 1994 Sep;1(6):501–508. doi: 10.1016/1074-7613(94)90092-2. [DOI] [PubMed] [Google Scholar]
  13. Grewal I. S., Xu J., Flavell R. A. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature. 1995 Dec 7;378(6557):617–620. doi: 10.1038/378617a0. [DOI] [PubMed] [Google Scholar]
  14. Guo Y., Wu Y., Zhao M., Kong X. P., Liu Y. Mutational analysis and an alternatively spliced product of B7 defines its CD28/CTLA4-binding site on immunoglobulin C-like domain. J Exp Med. 1995 Apr 1;181(4):1345–1355. doi: 10.1084/jem.181.4.1345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hathcock K. S., Hirano H., Murakami S., Hodes R. J. CD44 expression on activated B cells. Differential capacity for CD44-dependent binding to hyaluronic acid. J Immunol. 1993 Dec 15;151(12):6712–6722. [PubMed] [Google Scholar]
  16. Hathcock K. S., Hirano H., Murakami S., Hodes R. J. CD44 expression on activated B cells. Differential capacity for CD44-dependent binding to hyaluronic acid. J Immunol. 1993 Dec 15;151(12):6712–6722. [PubMed] [Google Scholar]
  17. Jalkanen S., Jalkanen M. Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin. J Cell Biol. 1992 Feb;116(3):817–825. doi: 10.1083/jcb.116.3.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kennedy M. K., Mohler K. M., Shanebeck K. D., Baum P. R., Picha K. S., Otten-Evans C. A., Janeway C. A., Jr, Grabstein K. H. Induction of B cell costimulatory function by recombinant murine CD40 ligand. Eur J Immunol. 1994 Jan;24(1):116–123. doi: 10.1002/eji.1830240118. [DOI] [PubMed] [Google Scholar]
  19. Lafferty K. J., Prowse S. J., Simeonovic C. J., Warren H. S. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu Rev Immunol. 1983;1:143–173. doi: 10.1146/annurev.iy.01.040183.001043. [DOI] [PubMed] [Google Scholar]
  20. Lesley J., Hyman R., Kincade P. W. CD44 and its interaction with extracellular matrix. Adv Immunol. 1993;54:271–335. doi: 10.1016/s0065-2776(08)60537-4. [DOI] [PubMed] [Google Scholar]
  21. Liu D., Sy M. S. A cysteine residue located in the transmembrane domain of CD44 is important in binding of CD44 to hyaluronic acid. J Exp Med. 1996 May 1;183(5):1987–1994. doi: 10.1084/jem.183.5.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Liu Y., Linsley P. S. Costimulation of T-cell growth. Curr Opin Immunol. 1992 Jun;4(3):265–270. doi: 10.1016/0952-7915(92)90075-p. [DOI] [PubMed] [Google Scholar]
  23. Lokeshwar V. B., Fregien N., Bourguignon L. Y. Ankyrin-binding domain of CD44(GP85) is required for the expression of hyaluronic acid-mediated adhesion function. J Cell Biol. 1994 Aug;126(4):1099–1109. doi: 10.1083/jcb.126.4.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Metlay J. P., Witmer-Pack M. D., Agger R., Crowley M. T., Lawless D., Steinman R. M. The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies. J Exp Med. 1990 May 1;171(5):1753–1771. doi: 10.1084/jem.171.5.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  26. Naujokas M. F., Morin M., Anderson M. S., Peterson M., Miller J. The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44. Cell. 1993 Jul 30;74(2):257–268. doi: 10.1016/0092-8674(93)90417-o. [DOI] [PubMed] [Google Scholar]
  27. Naujokas M. F., Morin M., Anderson M. S., Peterson M., Miller J. The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44. Cell. 1993 Jul 30;74(2):257–268. doi: 10.1016/0092-8674(93)90417-o. [DOI] [PubMed] [Google Scholar]
  28. Puré E., Camp R. L., Peritt D., Panettieri R. A., Jr, Lazaar A. L., Nayak S. Defective phosphorylation and hyaluronate binding of CD44 with point mutations in the cytoplasmic domain. J Exp Med. 1995 Jan 1;181(1):55–62. doi: 10.1084/jem.181.1.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ranheim E. A., Kipps T. J. Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J Exp Med. 1993 Apr 1;177(4):925–935. doi: 10.1084/jem.177.4.925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rothman B. L., Blue M. L., Kelley K. A., Wunderlich D., Mierz D. V., Aune T. M. Human T cell activation by OKT3 is inhibited by a monoclonal antibody to CD44. J Immunol. 1991 Oct 15;147(8):2493–2499. [PubMed] [Google Scholar]
  31. Roy M., Aruffo A., Ledbetter J., Linsley P., Kehry M., Noelle R. Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses. Eur J Immunol. 1995 Feb;25(2):596–603. doi: 10.1002/eji.1830250243. [DOI] [PubMed] [Google Scholar]
  32. Schultze J. L., Cardoso A. A., Freeman G. J., Seamon M. J., Daley J., Pinkus G. S., Gribben J. G., Nadler L. M. Follicular lymphomas can be induced to present alloantigen efficiently: a conceptual model to improve their tumor immunogenicity. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8200–8204. doi: 10.1073/pnas.92.18.8200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Seed B., Aruffo A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc Natl Acad Sci U S A. 1987 May;84(10):3365–3369. doi: 10.1073/pnas.84.10.3365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Shahinian A., Pfeffer K., Lee K. P., Kündig T. M., Kishihara K., Wakeham A., Kawai K., Ohashi P. S., Thompson C. B., Mak T. W. Differential T cell costimulatory requirements in CD28-deficient mice. Science. 1993 Jul 30;261(5121):609–612. doi: 10.1126/science.7688139. [DOI] [PubMed] [Google Scholar]
  35. Toyama-Sorimachi N., Sorimachi H., Tobita Y., Kitamura F., Yagita H., Suzuki K., Miyasaka M. A novel ligand for CD44 is serglycin, a hematopoietic cell lineage-specific proteoglycan. Possible involvement in lymphoid cell adherence and activation. J Biol Chem. 1995 Mar 31;270(13):7437–7444. doi: 10.1074/jbc.270.13.7437. [DOI] [PubMed] [Google Scholar]
  36. Wayner E. A., Carter W. G. Identification of multiple cell adhesion receptors for collagen and fibronectin in human fibrosarcoma cells possessing unique alpha and common beta subunits. J Cell Biol. 1987 Oct;105(4):1873–1884. doi: 10.1083/jcb.105.4.1873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wu Y., Guo Y., Liu Y. A major costimulatory molecule on antigen-presenting cells, CTLA4 ligand A, is distinct from B7. J Exp Med. 1993 Nov 1;178(5):1789–1793. doi: 10.1084/jem.178.5.1789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wu Y., Xu J., Shinde S., Grewal I., Henderson T., Flavell R. A., Liu Y. Rapid induction of a novel costimulatory activity on B cells by CD40 ligand. Curr Biol. 1995 Nov 1;5(11):1303–1311. doi: 10.1016/s0960-9822(95)00257-0. [DOI] [PubMed] [Google Scholar]
  39. Xu J., Foy T. M., Laman J. D., Elliott E. A., Dunn J. J., Waldschmidt T. J., Elsemore J., Noelle R. J., Flavell R. A. Mice deficient for the CD40 ligand. Immunity. 1994 Aug;1(5):423–431. doi: 10.1016/1074-7613(94)90073-6. [DOI] [PubMed] [Google Scholar]
  40. Yang B., Yang B. L., Savani R. C., Turley E. A. Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. EMBO J. 1994 Jan 15;13(2):286–296. doi: 10.1002/j.1460-2075.1994.tb06261.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. van Essen D., Kikutani H., Gray D. CD40 ligand-transduced co-stimulation of T cells in the development of helper function. Nature. 1995 Dec 7;378(6557):620–623. doi: 10.1038/378620a0. [DOI] [PubMed] [Google Scholar]

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