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The costimulation-regulated duration of PKB activation controls T cell longevity

  • A Corrigendum to this article was published on 01 November 2004

Abstract

A brief antigenic stimulus can promote T cell proliferation, but the duration and nature of intracellular signals required for survival are unclear. Here we show that in the absence of OX40 costimulation, antigen-activated CD4+ cells are short-lived because the activity of protein kinase B (PKB; also known as Akt) is not maintained over time. Activated T cells that express a dominant-negative variant of PKB also undergo apoptosis, reproducing the OX40-deficient phenotype. In contrast, an active form of PKB prevents downregulation of antiapoptotic proteins in OX40-deficient T cells, rescues antigen-induced cell survival in vivo, and controls inflammation in recall responses. Thus, sustained and periodic PKB signaling has an integral role in regulating T cell longevity.

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References

  1. 1

    Weiss, A., Shields, R., Newton, M., Manger, B. & Imboden, J. Ligand-receptor interactions required for commitment to the activation of the interleukin 2 gene. J. Immunol. 138, 2169–2176 (1987).

  2. 2

    Iezzi, G., Karjalainen, K. & Lanzavecchia, A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8, 89–95 (1998).

  3. 3

    van Stipdonk, M.J., Lemmens, E.E. & Schoenberger, S.P. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat. Immunol. 2, 423–429 (2001).

  4. 4

    Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003).

  5. 5

    Gramaglia, I. et al. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J. Immunol. 165, 3043–3050 (2000).

  6. 6

    Rogers, P.R., Song, J., Gramaglia, I., Killeen, N. & Croft, M. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 15, 445–455 (2001).

  7. 7

    Cooper, D., Bansal-Pakala, P. & Croft, M. 41BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity. Eur. J. Immunol. 32, 521–529 (2002).

  8. 8

    Boise, L.H. et al. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL . Immunity 3, 87–98 (1995).

  9. 9

    Dahl, A.M. et al. Expression of bcl-XL restores cell survival, but not proliferation or effector differentiation, in CD28-deficient T lymphocytes. J. Exp. Med. 191, 2031–2038 (2000).

  10. 10

    Van Parijs, L. et al. Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. Immunity 11, 281–288 (1999).

  11. 11

    Salek-Ardakani, S. et al. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. J. Exp. Med. 198, 315–324 (2003).

  12. 12

    Gramaglia, I., Weinberg, A.D., Lemon, M. & Croft, M. Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J. Immunol. 161, 6510–6517 (1998).

  13. 13

    Ohshima, Y. et al. Expression and function of OX40 ligand on human dendritic cells. J. Immunol. 159, 3838–3848 (1997).

  14. 14

    Dudek, H. et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275, 661–665 (1997).

  15. 15

    del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R. & Nunez, G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278, 687–689 (1997).

  16. 16

    Parsons, M.J. et al. Expression of active protein kinase B in T cells perturbs both T and B cell homeostasis and promotes inflammation. J. Immunol. 167, 42–48 (2001).

  17. 17

    Jones, R.G. et al. Protein kinase B regulates T lymphocyte survival, nuclear factor κB activation, and Bcl-XL levels in vivo. J. Exp. Med. 191, 1721–1734 (2000).

  18. 18

    Rathmell, J.C., Elstrom, R.L., Cinalli, R.M. & Thompson, C.B. Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma. Eur. J. Immunol. 33, 2223–2232 (2003).

  19. 19

    Parry, R.V. et al. Ligation of the T cell co-stimulatory receptor CD28 activates the serine-threonine protein kinase protein kinase B. Eur. J. Immunol. 27, 2495–2501 (1997).

  20. 20

    Kane, L.P., Andres, P.G., Howland, K.C., Abbas, A.K. & Weiss, A. Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-γ but not TH2 cytokines. Nat. Immunol. 2, 37–44 (2001).

  21. 21

    Jones, R.G. et al. CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. J. Exp. Med. 196, 335–348 (2002).

  22. 22

    Ahmed, N.N., Grimes, H.L., Bellacosa, A., Chan, T.O. & Tsichlis, P.N. Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc. Natl. Acad. Sci. USA 94, 3627–3632 (1997).

  23. 23

    Kelly, E., Won, A., Refaeli, Y. & Van Parijs, L. IL-2 and related cytokines can promote T cell survival by activating AKT. J. Immunol. 168, 597–603 (2002).

  24. 24

    Cross, D.A., Alessi, D.R., Cohen, P., Andjelkovich, M. & Hemmings, B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995).

  25. 25

    Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).

  26. 26

    Franke, T.F., Kaplan, D.R., Cantley, L.C. & Toker, A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 275, 665–668 (1997).

  27. 27

    Songyang, Z., Baltimore, D., Cantley, L.C., Kaplan, D.R. & Franke, T.F. Interleukin 3-dependent survival by the Akt protein kinase. Proc. Natl. Acad. Sci. USA 94, 11345–11350 (1997).

  28. 28

    Jember, A.G., Zuberi, R., Liu, F.T. & Croft, M. Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40. J. Exp. Med. 193, 387–392 (2001).

  29. 29

    Gunzer, M. et al. Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity 13, 323–332 (2000).

  30. 30

    Miller, M.J., Wei, S.H., Parker, I. & Cahalan, M.D. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296, 1869–1873 (2002).

  31. 31

    Stoll, S., Delon, J., Brotz, T.M. & Germain, R.N. Dynamic imaging of T cell–dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002).

  32. 32

    Linton, P.J. et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo. J. Exp. Med. 197, 875–883 (2003).

  33. 33

    Kim, M.Y. et al. CD4+CD3 accessory cells costimulate primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B cells. Immunity 18, 643–654 (2003).

  34. 34

    Arimura, Y. et al. A co-stimulatory molecule on activated T cells, H4/ICOS, delivers specific signals in Th cells and regulates their responses. Int. Immunol. 14, 555–566 (2002).

  35. 35

    Pugazhenthi, S. et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J. Biol. Chem. 275, 10761–10766 (2000).

  36. 36

    Burgering, B.M. & Kops, G.J. Cell cycle and death control: long live Forkheads. Trends Biochem. Sci. 27, 352–360 (2002).

  37. 37

    Pap, M. & Cooper, G.M. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J. Biol. Chem. 273, 19929–19932 (1998).

  38. 38

    Datta, S.R., Brunet, A. & Greenberg, M.E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999).

  39. 39

    Stahl, M. et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J. Immunol. 168, 5024–5031 (2002).

  40. 40

    Dijkers, P.F. et al. FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity. J. Cell Biol. 156, 531–542 (2002).

  41. 41

    Datta, S.R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241 (1997).

  42. 42

    Plas, D.R., Talapatra, S., Edinger, A.L., Rathmell, J.C. & Thompson, C.B. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J. Biol. Chem. 276, 12041–12048 (2001).

  43. 43

    Frauwirth, K.A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002).

  44. 44

    Zhang, X., Sun, S., Hwang, I., Tough, D.F. & Sprent, J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8, 591–599 (1998).

  45. 45

    Schluns, K.S., Kieper, W.C., Jameson, S.C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).

  46. 46

    Ku, C.C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000).

  47. 47

    Seddon, B., Tomlinson, P. & Zamoyska, R. Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat. Immunol. 4, 680–686 (2003).

  48. 48

    Barnden, M.J., Allison, J., Heath, W.R. & Carbone, F.R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

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Acknowledgements

This work was supported by grants from the NIH (CA91827 and AI50498) and the Sandler Program for Asthma Research (to Mi.C.). This is manuscript number 534 from the La Jolla Institute for Allergy and Immunology.

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Competing interests

The authors declare no competing financial interests.

Correspondence to Michael Croft.

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Further reading

Figure 1: OX40 signals maintain PKB phosphorylation over time and are required for long-term survival of antigen-stimulated CD4+ cells.
Figure 2: OX40 signals sustain PKB kinase activity.
Figure 3: Retroviral transduction of OX40-deficient T cells with active PKB reverses their survival defect.
Figure 4: PKB regulates the expression of Bcl-xL, Bcl-2 and Bfl-1 and suppresses apoptosis.
Figure 5: PKB restores the survival of OX40-deficient T cells in secondary responses in vitro.
Figure 6: Sustained PKB controls T cell survival in vivo.
Figure 7: Sustained PKB does not alter T cell reactivity in vivo.
Figure 8: Sustained PKB restores the ability of OX40-deficient T cells to promote lung inflammation.