Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

B and T lymphocyte attenuator regulates CD8+ T cell–intrinsic homeostasis and memory cell generation

Nature Immunology volume 8, pages 162–171 (2007)Cite this article

Abstract

B and T lymphocyte attenuator (BTLA) is a negative regulator of T cell activation, but its function in vivo is not well characterized. Here we show that mice deficient in full-length BTLA or its ligand, herpesvirus entry mediator, had increased number of memory CD8+ T cells. The memory CD8+ T cell phenotype resulted from a T cell–intrinsic perturbation of the CD8+ T cell pool. Naive BTLA-deficient CD8+ T cells were more efficient than wild-type cells at generating memory in a competitive antigen-specific system. This effect was independent of the initial expansion of the responding antigen-specific T cell population. In addition, BTLA negatively regulated antigen-independent homeostatic expansion of CD4+ and CD8+ T cells. These results emphasize two central functions of BTLA in limiting T cell activity in vivo.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Naive and activated-memory BTLA-deficient T cells are not intrinsically hyperproliferative.
Figure 2: Increased CD8+ memory-phenotype T cells in BTLA-KO and HVEM-KO mice.
Figure 3: T cell–intrinsic increase in CD8+ memory-phenotype T cells in BTLA-KO mice.
Figure 4: In mixed bone marrow chimeras, rapid IFN-γ production correlates with the percentage of the CD44hi cell population.
Figure 5: BTLA-KO T cells outcompete wild-type T cells during homeostatic expansion.
Figure 6: More efficient antigen-specific CD8+ memory formation by BTLA-KO T cells in the absence of an enhanced primary response.
Figure 7: Enhanced acquisition of a typical memory-phenotype by BTLA-KO CD8+ T cells.
Figure 8: Secondary responses of BTLA-KO CD8+ memory T cells.

Similar content being viewed by others

References

  1. Min, B. et al. Neonates support lymphopenia-induced proliferation. Immunity 18, 131–140 (2003).

    Article  CAS  Google Scholar 

  2. Margolick, J.B. & Donnenberg, A.D. T-cell homeostasis in HIV-1 infection. Semin. Immunol. 9, 381–388 (1997).

    Article  CAS  Google Scholar 

  3. Dudley, M.E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).

    Article  CAS  Google Scholar 

  4. Goldrath, A.W. & Bevan, M.J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999).

    Article  CAS  Google Scholar 

  5. Ernst, B., Lee, D.S., Chang, J.M., Sprent, J. & Surh, C.D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 (1999).

    Article  CAS  Google Scholar 

  6. Ge, Q., Rao, V.P., Cho, B.K., Eisen, H.N. & Chen, J. Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/MHC epitopes and strength of their interaction with T cell receptors. Proc. Natl. Acad. Sci. USA 98, 1728–1733 (2001).

    Article  CAS  Google Scholar 

  7. Kennedy, M.K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15–deficient mice. J. Exp. Med. 191, 771–780 (2000).

    Article  CAS  Google Scholar 

  8. Prlic, M., Blazar, B.R., Khoruts, A., Zell, T. & Jameson, S.C. Homeostatic expansion occurs independently of costimulatory signals. J. Immunol. 167, 5664–5668 (2001).

    Article  CAS  Google Scholar 

  9. Carreno, B.M. & Collins, M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu. Rev. Immunol. 20, 29–53 (2002).

    Article  CAS  Google Scholar 

  10. Li, O., Zheng, P. & Liu, Y. CD24 expression on T cells is required for optimal T cell proliferation in lymphopenic host. J. Exp. Med. 200, 1083–1089 (2004).

    Article  CAS  Google Scholar 

  11. Greenwald, R.J., Freeman, G.J. & Sharpe, A.H. The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005).

    Article  Google Scholar 

  12. Watanabe, N. et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat. Immunol. 4, 670–679 (2003).

    Article  CAS  Google Scholar 

  13. Han, P., Goularte, O.D., Rufner, K., Wilkinson, B. & Kaye, J. An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J. Immunol. 172, 5931–5939 (2004).

    Article  CAS  Google Scholar 

  14. Sedy, J.R. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat. Immunol. 6, 90–98 (2005).

    Article  CAS  Google Scholar 

  15. Gonzalez, L.C. et al. A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Proc. Natl. Acad. Sci. USA 102, 1116–1121 (2005).

    Article  CAS  Google Scholar 

  16. Compaan, D.M. et al. Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex. J. Biol. Chem. 280, 39553–39561 (2005).

    Article  CAS  Google Scholar 

  17. Hurchla, M.A. et al. B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly Induced in anergic CD4+ T cells. J. Immunol. 174, 3377–3385 (2005).

    Article  CAS  Google Scholar 

  18. Otsuki, N., Kamimura, Y., Hashiguchi, M. & Azuma, M. Expression and function of the B and T lymphocyte attenuator (BTLA/CD272) on human T cells. Biochem. Biophys. Res. Commun. 344, 1121–1127 (2006).

    Article  CAS  Google Scholar 

  19. Tamada, K. et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nat. Med. 6, 283–289 (2000).

    Article  CAS  Google Scholar 

  20. Zhai, Y. et al. LIGHT, a novel ligand for lymphotoxin β receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J. Clin. Invest. 102, 1142–1151 (1998).

    Article  CAS  Google Scholar 

  21. Mauri, D.N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin α are ligands for herpesvirus entry mediator. Immunity 8, 21–30 (1998).

    Article  CAS  Google Scholar 

  22. Wang, Y. et al. The role of herpesvirus entry mediator as a negative regulator of T cell-mediated responses. J. Clin. Invest. 115, 711–717 (2005).

    Article  CAS  Google Scholar 

  23. Morel, Y. et al. Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor. J. Immunol. 165, 4397–4404 (2000).

    Article  CAS  Google Scholar 

  24. Cheung, T.C. et al. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proc. Natl. Acad. Sci. USA 102, 13218–13223 (2005).

    Article  CAS  Google Scholar 

  25. Krieg, C., Han, P., Stone, R., Goularte, O.D. & Kaye, J. Functional analysis of B and T lymphocyte attenuator engagement on CD4+ and CD8+ T cells. J. Immunol. 175, 6420–6427 (2005).

    Article  CAS  Google Scholar 

  26. Chemnitz, J.M., Lanfranco, A.R., Braunstein, I. & Riley, J.L. B and T lymphocyte attenuator–mediated signal transduction provides a potent inhibitory signal to primary human CD4 T cells that can be initiated by multiple phosphotyrosine motifs. J. Immunol. 176, 6603–6614 (2006).

    Article  CAS  Google Scholar 

  27. Deppong, C. et al. Cutting edge: B and T lymphocyte attenuator and programmed death receptor-1 inhibitory receptors are required for termination of acute allergic airway inflammation. J. Immunol. 176, 3909–3913 (2006).

    Article  CAS  Google Scholar 

  28. Tao, R. et al. Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts. J. Immunol. 175, 5774–5782 (2005).

    Article  CAS  Google Scholar 

  29. Tan, K.B. et al. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene 204, 35–46 (1997).

    Article  CAS  Google Scholar 

  30. Curtsinger, J.M., Lins, D.C. & Mescher, M.F. CD8+ memory T cells (CD44high, Ly-6C+) are more sensitive than naive cells to (CD44low, Ly-6C−) to TCR/CD8 signaling in response to antigen. J. Immunol. 160, 3236–3243 (1998).

    CAS  PubMed  Google Scholar 

  31. Sprent, J. & Surh, C.D. T cell memory. Annu. Rev. Immunol. 20, 551–579 (2002).

    Article  CAS  Google Scholar 

  32. Judge, A.D., Zhang, X., Fujii, H., Surh, C.D. & Sprent, J. Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8+ T cells. J Exp Med 196, 935–946 (2002).

    Article  CAS  Google Scholar 

  33. Boyman, O., Cho, J.H., Tan, J.T., Surh, C.D. & Sprent, J. A major histocompatibility complex class I–dependent subset of memory phenotype CD8+ cells. J. Exp. Med. 203, 1817–1825 (2006).

    Article  CAS  Google Scholar 

  34. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).

    Article  CAS  Google Scholar 

  35. Agarwal, S. & Rao, A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9, 765–775 (1998).

    Article  CAS  Google Scholar 

  36. Veiga-Fernandes, H., Walter, U., Bourgeois, C., McLean, A. & Rocha, B. Response of naive and memory CD8+ T cells to antigen stimulation in vivo. Nat. Immunol. 1, 47–53 (2000).

    Article  CAS  Google Scholar 

  37. Surh, C.D. & Sprent, J. Regulation of mature T cell homeostasis. Semin. Immunol 17, 183–191 (2005).

    Article  CAS  Google Scholar 

  38. Badovinac, V.P., Messingham, K.A., Jabbari, A., Haring, J.S. & Harty, J.T. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat. Med. 11, 748–756 (2005).

    Article  CAS  Google Scholar 

  39. Harty, J.T., Tvinnereim, A.R. & White, D.W. CD8+ T cell effector mechanisms in resistance to infection. Annu Rev Immunol 18, 275–308 (2000).

    Article  CAS  Google Scholar 

  40. Shen, H. et al. Compartmentalization of bacterial antigens: differential effects on priming of CD8 T cells and protective immunity. Cell 92, 535–545 (1998).

    Article  CAS  Google Scholar 

  41. Tamada, K. et al. Cutting edge: selective impairment of CD8+ T cell function in mice lacking the TNF superfamily member LIGHT. J. Immunol. 168, 4832–4835 (2002).

    Article  CAS  Google Scholar 

  42. Sedgmen, B.J., Dawicki, W., Gommerman, J.L., Pfeffer, K. & Watts, T.H. LIGHT is dispensable for CD4+ and CD8+ T cell and antibody responses to influenza A virus in mice. Int. Immunol. 18, 797–806 (2006).

    Article  CAS  Google Scholar 

  43. Hou, S., Hyland, L., Ryan, K.W., Portner, A. & Doherty, P.C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature 369, 652–654 (1994).

    Article  CAS  Google Scholar 

  44. Badovinac, V.P., Porter, B.B. & Harty, J.T. Programmed contraction of CD8+ T cells after infection. Nat. Immunol. 3, 619–626 (2002).

    Article  CAS  Google Scholar 

  45. Boyman, O., Kovar, M., Rubinstein, M.P., Surh, C.D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924–1927 (2006).

    Article  CAS  Google Scholar 

  46. Tan, J.T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl. Acad. Sci. USA 98, 8732–8737 (2001).

    Article  CAS  Google Scholar 

  47. 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).

    Article  CAS  Google Scholar 

  48. Vella, A.T., Dow, S., Potter, T.A., Kappler, J. & Marrack, P. Cytokine-induced survival of activated T cells in vitro and in vivo. Proc. Natl. Acad. Sci. USA 95, 3810–3815 (1998).

    Article  CAS  Google Scholar 

  49. Kuroda, K. et al. Implantation of IL-2-containing osmotic pump prolongs the survival of superantigen-reactive T cells expanded in mice injected with bacterial superantigen. J. Immunol. 157, 1422–1431 (1996).

    CAS  PubMed  Google Scholar 

  50. Shimizu, K., Fields, R.C., Giedlin, M. & Mule, J.J. Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines. Proc. Natl. Acad. Sci. USA 96, 2268–2273 (1999).

    Article  CAS  Google Scholar 

  51. Blattman, J.N. et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med. 9, 540–547 (2003).

    Article  CAS  Google Scholar 

  52. Williams, M.A., Tyznik, A.J. & Bevan, M.J. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441, 890–893 (2006).

    Article  CAS  Google Scholar 

  53. Reed, A.J. et al. The frequency of double-positive thymocytes expressing an αβ TCR clonotype regulates peripheral CD4 T cell compartment homeostasis. Immunology 116, 400–407 (2005).

    Article  CAS  Google Scholar 

  54. Hamilton, S.E., Wolkers, M.C., Schoenberger, S.P. & Jameson, S.C. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat. Immunol. 7, 475–481 (2006).

    Article  CAS  Google Scholar 

  55. 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).

    Article  CAS  Google Scholar 

  56. Lefrancois, L., Marzo, A.L., Masopust, D., Schluns, K.S. & Vezy, V. Migration of primary and memory CD8 T cells. Adv. Exp. Med. Biol. 512, 141–146 (2002).

    Article  Google Scholar 

  57. Murali-Krishna, K. et al. Persistence of memory CD8 T cells in MHC class I–deficient mice. Science 286, 1377–1381 (1999).

    Article  CAS  Google Scholar 

  58. Swain, S.L., Hu, H. & Huston, G. Class II–independent generation of CD4 memory T cells from effectors. Science 286, 1381–1383 (1999).

    Article  CAS  Google Scholar 

  59. Wang, J. et al. The critical role of LIGHT in promoting intestinal inflammation and Crohn's disease. J. Immunol. 174, 8173–8182 (2005).

    Article  CAS  Google Scholar 

  60. Hogquist, K.A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. Aliahmad and M. Fung for critically reviewing this manuscript, S. Freigang and J.T. Tan for discussion; N. Sanathara and O. Goularte for technical assistance; and the Department of Animal Resources and the Flow Cytometry Core Facility at The Scripps Research Institute for support. Supported by the National Institutes of Health (AI-31231 to J.K.), and the Swiss National Science Foundation and the Novartis Foundation (to O.B.). This is manuscript 18376 from the Scripps Research Institute.

Author information

Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Carsten Krieg, Onur Boyman & Jonathan Kaye

  2. Division of Immunology and Allergy, University Hospital of Lausanne, Lausanne, CH-1011, Switzerland

    Onur Boyman

  3. Department of Pathology, University of Chicago, Chicago, 60637, Illinois, USA

    Yang-Xin Fu

Authors
  1. Carsten Krieg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Onur Boyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang-Xin Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan Kaye
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.K. and O.B. did the experiments; C.K., O.B. and J.K. designed the experiments, interpreted the results and wrote the manuscript; and Y.-X.F. contributed reagents and helped with the manuscript.

Corresponding author

Correspondence to Jonathan Kaye.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

BTLA and HVEM expression on CD8+ T cell subsets. (PDF 59 kb)

Supplementary Fig. 2

Increased CD4 to CD8 T cell ratio in BTLA-KO and HVEM-KO mice. (PDF 63 kb)

Supplementary Fig. 3

BTLA expression on homeostatically expanded WT CD8+ OT-I Tg T cells. (PDF 67 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krieg, C., Boyman, O., Fu, YX. et al. B and T lymphocyte attenuator regulates CD8+ T cell–intrinsic homeostasis and memory cell generation. Nat Immunol 8, 162–171 (2007). https://doi.org/10.1038/ni1418

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1418

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing