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CD27 is required for generation and long-term maintenance of T cell immunity


The Traf-linked tumor necrosis factor receptor family member CD27 is known as a T cell costimulatory molecule. We generated CD27−/− mice and found that CD27 makes essential contributions to mature CD4+ and CD8+ T cell function: CD27 supported antigen-specific expansion (but not effector cell maturation) of naïve T cells, independent of the cell cycle–promoting activities of CD28 and interleukin 2. Primary CD4+ and CD8+ T cell responses to influenza virus were impaired in CD27−/− mice. Effects of deleting the gene encoding CD27 were most profound on T cell memory, reflected by delayed response kinetics and reduction of CD8+ virus-specific T cell numbers to the level seen in the primary response. This demonstrates the requirement for a costimulatory receptor in the generation of T cell memory.

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  1. 1

    Arch, R. H., Gedrich, R. W. & Thompson, C. B. Tumor necrosis factor receptor-associated factors (TRAFs)- a family of adapter proteins that regulates life and death. Genes Dev. 12, 2821–2830 (1998).

  2. 2

    Gravestein, L. A. & Borst, J. Tumor necrosis factor receptor family members in the immune response. Sem. Immunol. 10, 423–434 (1998).

  3. 3

    Anderson, D. M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175–179 (1997).

  4. 4

    Koch, F. et al. High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-10. J. Exp. Med. 184, 741–746 (1996).

  5. 5

    Grell, M. et al. Induction of cell death by tumor necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF. EMBO J. 18, 3034–3043 (1999).

  6. 6

    Xu, Y., Cheng, G. & Baltimore, D. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity 5, 407–415 (1996).

  7. 7

    Yeh, W.-C. et al. Early lethality, functional NF-κB activation & increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7, 715–725 ( 1997).

  8. 8

    Lee, S. Y., Reichlin, A., Santana, A., Sokol. K. A. Nussenzweig, M. C. & Choi, Y. TRAF2 is essential for JNK but not NF-κB activation and regulates lymphocyte proliferation and survival. Immunity 7, 703–713 (1997).

  9. 9

    Rothe, M., Pan, M.G., Henzel, W. J., Ayres, T. M. & Goeddel, D. V. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83, 1243–1252 ( 1995).

  10. 10

    Liu, Z.-G. Hsu, H., Goeddel, D. V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87 , 565–576 (1996).

  11. 11

    Camerini, D., Walz, G., Loenen, W. A. M., Borst, J. & Seed, B. The T cell activation antigen CD27 is a member of the NGF/TNF receptor gene family. J. Immunol. 147, 3165–3169 (1991).

  12. 12

    Gravestein, L. A. et al. Cloning and expression of murine CD27: comparison with 4-1BB another lymphocyte-specific member of the nerve growth factor receptor family . Eur. J. Immunol. 23, 943– 950 (1993).

  13. 13

    Goodwin, R.G. et al. Molecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor . Cell 73, 447–456 (1993).

  14. 14

    Bowman, M.R. et al. The cloning of CD70 and its identification as the ligand for CD27. J. Immunol. 152, 1756– 1761 (1994).

  15. 15

    Tesselaar, K., Gravestein, L. A., van Schijndel, G. M.W., Borst, J. & van Lier, R.A. W. Characterizaton of murine CD70, the ligand of the TNF receptor family member CD27. J. Immunol. 159, 4959–4965 ( 1997).

  16. 16

    Oshima, H. et al. Characterization of murine CD70 by molecular cloning and mAb . Int. Immunol. 10, 517– 526 (1998).

  17. 17

    Lens, S. M., Tesselaar, K., van Oers, M. H. J. & van Lier, R.A. W. Control of lymphocyte function through CD27–CD70 interactions. Sem. Immunol. 10, 491–499 (1998).

  18. 18

    Van Lier, R.A. W. et al. Tissue distribution and biochemical and functional properties of Tp55 (CD27), an novel T cell differentiation antigen. J. Immunol. 139, 1589–1596 ( 1987).

  19. 19

    Hintzen, R. Q., de Jong, R., Lens, S. M.A. & van Lier, R.A. W. CD27: marker and mediator of T-cell activation. Immunol. Today 15, 307–311 ( 1994).

  20. 20

    Gravestein, L. A., Nieland, J. D., Kruisbeek, A. M. & Borst, J. Novel mAbs reveal potent co-stimulatory activity of murine CD27. Int. Immunol. 7, 551–557 (1995).

  21. 21

    Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186 , 1–12 (1997).

  22. 22

    Maurer, D. et al. IgM and IgG but not cytokine secretion is restricted to the CD27+ B lymphocyte subset. J. Immunol. 148, 3700–3705 (1992).

  23. 23

    Klein, U., Rajewsky, K. & Kuppers, R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J. Exp. Med. 188, 1679–1689 (1998).

  24. 24

    Vinay, D. S. & Kwon, B. S. Role of 4-1BB in immune responses . Sem. Immunol. 10, 481– 489 (1998).

  25. 25

    Weinberg, A. D., Vella, A. T. & Croft, M. OX-40: life beyond the effector T cell stage. Sem. Immunol. 10, 471–480 (1998).

  26. 26

    Hintzen, R.Q. et al. CD70 represents the human ligand for CD27. Int. Immunol. 6, 477–480 ( 1994).

  27. 27

    Akiba, H. et al. Critical contribution of OX40 ligand to T helper cell type 2 differentiation in experimental leishmaniasis. J. Exp. Med. 191, 375–380 (2000).

  28. 28

    Kobata, T., Agematsu, K., Kameoka, J., Schlossman, S. F., Morimoto, C. CD27 is a signal-transducing molecule involved in CD45RA+ naïve T cell costimulation. J. Immunol. 153, 5422–5432 ( 1994).

  29. 29

    Hintzen, R.Q. et al. Engagement of CD27 with its ligand CD70 provides a second signal for T cell activation. J. Immunol. 154, 2612–2623 (1995).

  30. 30

    Brown, G. R., Meek, K., Nishioka, Y. & Thiele, D. L. CD27-CD27ligand/CD70 interactions enhance alloantigen-induced proliferation and cytolytic activity in CD8+ T lymphocytes. J. Immunol. 154 , 3686–3695 (1995).

  31. 31

    Agematsu, K. et al. Generation of plasma cells from peripheral blood memory B cells: Synergistic effect of interleukin-10 and CD27/CD70 interaction. Blood 91, 173–180 ( 1998).

  32. 32

    Lenschow, D. J., Walunas, T. L. & Bluestone, J.A. CD28/B7 system of T cell co-stimulation. Annu. Rev. Immunol. 14: 233–258 (1996).

  33. 33

    Flynn, K.J. et al. Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity 8, 683–691 (1998).

  34. 34

    Haanen, J. B.A. G. Wolkers, M., Kruisbeek, A. M. & Schumacher, T. N.M. Selective expansion of cross-reactive CD8+ memory T cells by viral variants. J. Exp. Med. 190, 1319– 1328 (1999).

  35. 35

    Gravestein, L. A., van Ewijk, W., Ossendorp, F. & Borst, J. CD27 cooperates with the pre-T cell receptor in the regulation of murine T cell development. J. Exp. Med. 184, 675– 685 (1996).

  36. 36

    Gravestein, L.A. et al. The Tumor Necrosis Factor receptor family member CD27 signals to Jun N-terminal kinase via Traf-2. Eur. J. Immunol 28, 2208–2216 (1998).

  37. 37

    Akiba, H. et al. CD27, a member of the Tumor Necrosis Factor receptor superfamily, activates NF-kappaB and Stress-activated protein kinase/c-Jun N-terminal kinase via TRAF-2, TRAF-5 and NF-kappaB-inducing kinase. J. Biol. Chem. 273, 13353–13358 ( 1998).

  38. 38

    Nakano, H. et al. Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation. Proc. Natl. Acad. Sci. USA 96, 9803–9808 ( 1999).

  39. 39

    Grewal, I.S Xu, J. & Flavell, R.A. Impairment of antigen-specific T cell priming in mice lacking CD40 ligand. Nature 378, 617– 620 (1995).

  40. 40

    Schoenberger, S. P., Toes, R. E. M., van der Voort, E. I. H. Offringa, R. & Melief, C. J. M. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393, 480–483 (1998).

  41. 41

    Bennett, S. R. M. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling . Nature 393, 478–480 (1998).

  42. 42

    DeBenedette, M., Wen T., Bachmann, M., Ohashi, P. S., Barber, B. H., Stocking, K. L., Peschon, J. J. & Watts, T. Analysis of 4-1BB Ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus. J. Immunol. 163, 4833–4841 (1999).

  43. 43

    Tan, J. T., Whitmire, J. K., Ahmed, R., Pearson, T. C. & Larsen, C. P. 4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T cell responses . J. Immunol. 163, 4859– 4868 (1999).

  44. 44

    Kopf, M., Ruedl, C., Schmitz, N., Gallimore, A., Lefrang, K., Ecabert, B., Odermatt, B. & Bachmann, M.F. OX40-deficient mice are defective in Th cell proliferation but are competent in generating B cell and CTL responses after virus infection . Immunity 11, 699–708 (1999).

  45. 45

    Murata, K., Ishii, N., Takano, H., Miura, S., Ndhlovu, L. C., Nose, M., Noda, T. & Sugamura, K. Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand. J. Exp. Med. 191 , 365–374 (2000).

  46. 46

    Shahinian, A. et al. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261, 609– 612 (1993).

  47. 47

    Whitmire, J.K. et al. CD40 ligand-deficient mice generate a normal primary cytotoxic T-lymphocyte response but a defective humoral response to a viral infection . J. Virol. 70, 8375–8381 (1996).

  48. 48

    Oxenius, A. et al. CD40-CD40 ligand interactions are critical in T-B cooperation but not for other anti-viral CD4+ T cell functions. J. Exp. Med. 183, 2209–2218 (1996).

  49. 49

    Liu, Y., Wenger, R. H., Zhao, M. & Nielsen, P.J. Distinct costimulatory molecules are required for the induction of effector and memory cytotoxic T cell responses. J. Exp. Med. 185, 251– 262 (1997).

  50. 50

    Lumsden, J. M., Roberts, J. M., Harris, N. L., Peach, R. J. & Ronchese, F. Differential requirement for CD80 and CD80/CD86-dependent costimulation in the lung immune response to influenza virus. J. Immunol. 164, 79– 85 (2000).

  51. 51

    Chen, A. I., McAdam, A. J., Buhlmann, J. E., Scott, S., Lupher, M. L., Greenfield, E. A., Baum, P. R., Fanslow, W. C., Calderhead, D. M., Freeman, G. J. & Sharpe, A.H. Ox40-ligand has a critical costimulatory role in dendritic cell:T cell interactions. Immunity 11, 689–698 (1999).

  52. 52

    Borrow P., Tishon, A., Lee, S., Xu, J., Grewal, I. S., Oldstone, B. A. & Flavell, R. A. CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J. Exp. Med. 183, 2129–2142 (1996).

  53. 53

    Maxwell, J. R., Weinberg, A., Prell, R. A. & Vella, A. T. Danger and OX40 receptor synergize to enhance memory T cell survival by inhibiting peripheral deletion. J. Immunol. 164, 107 –112 (2000).

  54. 54

    Walker, L.S. K. et al. Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers. J. Exp. Med. 190, 1115– 1122 (1999).

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We thank E. Tanger, M. Timpico, L. Tolkamp, T. Schrauwers, H. Starrevelt and other staff of the Animal Facility of the Netherlands Cancer Institute for biotechnical assistance and maintenance of the mice; A. A. M. Hart for expert statistical analysis; G. Rimmelzwaan for virus preparations and advice; E. Noteboom and A. Pfauth for assistance with flow cytometry; P. Krimpenfort, J. Haanen, G. Dingjan, R. Hendriks and J. Kirberg for experimental advise and assistance; and A. M. Kruisbeek for reading the manuscript. Supported by The Netherlands Organization for Scientific Research (NWO).

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Correspondence to Jannie Borst.

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Web Figure 1

CD27 does not contribute to cytolytic effector cell maturation. Cytotoxicity of spleen cells from infected mice. Spleen cells collected from CD27 +/+ (closed squares) and CD27-/- (open squares) mice infection were cultured for 7 days with NP(366-374) peptide and IL-2. Next, cells were tested for specific cytotoxicity towards EL-4 thymoma cells, loaded with NP(366-374) peptide in a standard 5-h 51Cr-release assay at the indicated effector (E) to target (T) cell ratios. Activity on EL-4 targets without peptide was negligible. Values represent means and standard deviations of triplicate samples in one experiment. The experiment is representative of three. Spleen cells were collected from mice at day 14 after primary infection (upper panel) or at day 11 after secondary infection (lower panel).

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Figure 1: Tnfrsf7-targeting strategy and result.
Figure 2: CD27 does not affect T cell division.
Figure 3: CD27 is important for generation of T cell immunity to influenza virus.
Figure 4: CD27 is required for T cell memory.
Figure 5: CD27 contributes to the antigen-specific CD4+ T cell response.