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:

Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo

Abstract

We studied here the long-term maintenance of distinct populations of T helper type 1 (TH1)-lineage cells in vivo and found that effector TH1 cells, defined by their secretion of interferon-γ (IFN-γ), are short-lived and do not efficiently develop into long-term memory TH1 cells. In contrast, a population of activated TH1-lineage cells that did not secrete IFN-γ after primary antigenic stimulation persisted for several months in vivo and developed the capacity to secrete IFN-γ upon subsequent stimulation. These data suggest that a linear differentiation pathway, as defined by the transition from IFN-γ–producing to resting memory cells, is relatively limited in vivo and support a revised model for TH1 memory differentiation.

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

Access options

Buy this article

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

Figure 1: Survival of TH 1 effector cells in vivo after adoptive transfer.
Figure 2: Characterization and isolation of IFN-γ+ and IFN-γ cells from TH1 week 1 cultures.
Figure 3: The fate of IFN-γ+ and IFN-γ cells generated in vivo after adoptive transfer.

Similar content being viewed by others

References

  1. Abbas, A.K., Murphy, K.M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. O'Garra, A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8, 275–283 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Murphy, K.M. et al. Signaling and transcription in T helper development. Annu. Rev. Immunol. 18, 451–494 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Mullen, A.C. et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292, 1907–1910 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Dutton, R.W., Bradley, L.M. & Swain, S.L. T cell memory. Annu. Rev. Immunol. 16, 201–223 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Swain, S.L. Generation and in vivo persistence of polarized TH1 and TH2 memory cells. Immunity 1, 543–552 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. Trinchieri, G. Immunobiology of interleukin-12. Immunol. Res. 17, 269–278 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Stobie, L. et al. The role of antigen and IL-12 in sustaining TH1 memory cells in vivo: IL-12 is required to maintain memory/effector TH1 cells sufficient to mediate protection to an infectious parasite challenge. Proc. Natl. Acad. Sci. USA 97, 8427–8432 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Park, A.Y., Hondowicz, B.D. & Scott, P. IL-12 is required to maintain a TH1 response during Leishmania major infection. J. Immunol. 165, 896–902 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Yap, G., Pesin, M. & Sher, A. IL-12 is required for the maintenance of IFN-γ production in T cells mediating chronic resistance to the intracellular pathogen, Toxoplasma gondii. J. Immunol. 165, 628–631 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Leonard, J.P., Waldburger, K.E. & Goldman, S.J. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J. Exp. Med. 181, 381–386 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Neurath, M.F., Fuss, I., Kelsall, B.L., Stuber, E. & Strober, W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med. 182, 1281–1290 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Tarrant, T.K., Silver, P.B., Chan, C.C., Wiggert, B. & Caspi, R.R. Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis. J. Immunol. 161, 122–127 (1998).

    CAS  PubMed  Google Scholar 

  17. Hong, K., Berg, E.L. & Ehrhardt, R.O. Persistence of pathogenic CD4+ TH1-like cells in vivo in the absence of IL-12 but in the presence of autoantigen. J. Immunol. 166, 4765–4772 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Mendel, I. & Shevach, E.M. Differentiated TH1 autoreactive effector cells can induce experimental autoimmune encephalomyelitis in the absence of IL-12 and CD40/CD40L interactions. J. Neuroimmunol. 122, 65–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Hu-Li, J., Huang, H., Ryan, J. & Paul, W.E. In differentiated CD4+ T cells, interleukin 4 production is cytokine-autonomous, whereas interferon γ production is cytokine dependent. Proc. Natl. Acad. Sci. USA 94, 3189–3194 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rogers, P.R., Dubey, C. & Swain, S.L. Qualitative changes accompany memory T cell generation: faster, more effective responses at lower doses of antigen. J. Immunol. 164, 2338–2346 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Openshaw, P. et al. Heterogeneity of intracellular cytokine synthesis at the single-cell level in polarized T helper 1 and T helper 2 populations. J. Exp. Med. 182, 1357–1367 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Harbertson, J., Biederman, E., Bennett, K.E., Kondrack, R.M. & Bradley, L.M. Withdrawal of stimulation may initiate the transition of effector to memory CD4 cells. J. Immunol. 168, 1095–1102 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Ahmadzadeh, M., Hussain, S.F. & Farber, D.L. Heterogeneity of the memory CD4 T cell response: persisting effectors and resting memory T cells. J. Immunol. 166, 926–935 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Bucy, R.P. et al. Single cell analysis of cytokine gene coexpression during CD4+ T-cell phenotype development. Proc. Natl. Acad. Sci. USA 92, 7565–7569 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Scheffold, A. et al. Analysis and sorting of T cells according to cytokine expression. Eur. Cytokine Netw. 9, 5–11 (1998).

    CAS  PubMed  Google Scholar 

  26. Iezzi, G., Scheidegger, D. & Lanzavecchia, A. Migration and function of antigen-primed nonpolarized T lymphocytes in vivo. J. Exp. Med. 193, 987–993 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hu, H. et al. CD4+ T cell effectors can become memory cells with high efficiency and without further division. Nature Immunol. 2, 705–710 (2001).

    Article  CAS  Google Scholar 

  28. Reinhardt, R.L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M.K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Szabo, S.J. et al. A novel transcription factor, T-bet, directs TH1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Szabo, S.J., Dighe, A.S., Gubler, U. & Murphy, K.M. Regulation of the interleukin (IL)-12Rβ2 subunit expression in developing T helper 1 (TH1) and TH2 cells. J. Exp. Med. 185, 817–824 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zheng, W. & Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for TH2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Dalton, D.K. et al. Multiple defects of immune cell function in mice with disrupted interferon-γ genes. Science 259, 1739–1742 (1993).

    Article  CAS  PubMed  Google Scholar 

  35. Zhang, X. et al. Unequal death in T helper cell (TH)1 and TH2 effectors: TH1, but not TH2, effectors undergo rapid Fas/FasL-mediated apoptosis. J. Exp. Med. 185, 1837–1849 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Opferman, J.T., Ober, B.T. & Ashton-Rickardt, P.G. Linear differentiation of cytotoxic effectors into memory T lymphocytes. Science 283, 1745–1748 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Jacob, J. & Baltimore, D. Modelling T-cell memory by genetic marking of memory T cells in vivo. Nature 399, 593–597 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Homann, D., Teyton, L. & Oldstone, M.B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nature Med. 7, 913–919 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Gett, A.V. & Hodgkin, P.D. Cell division regulates the T cell cytokine repertoire, revealing a mechanism underlying immune class regulation. Proc. Natl. Acad. Sci. USA 95, 9488–9493 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bird, J.J. et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Richter, A., Lohning, M. & Radbruch, A. Instruction for cytokine expression in T helper lymphocytes in relation to proliferation and cell cycle progression. J. Exp. Med. 190, 1439–1450 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Grogan, J.L. et al. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14, 205–215 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Wang, X. & Mosmann, T. In vivo priming of CD4 T cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-γ, and can subsequently differentiate into IL-4- or IFN-γ-secreting cells. J. Exp. Med. 194, 1069–1080 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Panus, J.F., McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. Antigen-specific T helper cell function: differential cytokine expression in primary and memory responses. J. Exp. Med. 192, 1301–1316 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hayashi, N., Liu, D., Min, B., Ben-Sasson, S.Z. & Paul, W.E. Antigen challenge leads to in vivo activation and elimination of highly polarized TH1 memory T cells. Proc. Natl. Acad. Sci. USA 99, 6187–6191 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gurunathan, S., Prussin, C., Sacks, D.L. & Seder, R.A. Vaccine requirements for sustained cellular immunity to an intracellular parasitic infection. Nature Med. 4, 1409–1415 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. 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  PubMed  Google Scholar 

  48. Huygen, K. et al. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine. Nature Med. 2, 893–898 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Rhee, E.G. et al. Vaccination with heat-killed leishmania antigen or recombinant leishmanial protein and CpG oligodeoxynucleotides induces long-term memory CD4+ and CD8+ T cell responses and protection against Leishmania major infection. J. Exp. Med. 195, 1565–1573 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pfaffl, M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, 45–45 (2001).

    Article  Google Scholar 

Download references

Acknowledgements

We thank B. Marshal for editorial assistance and X. Tai for technical help with cell preparation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert A. Seder.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, Cy., Kirman, J., Rotte, M. et al. Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo. Nat Immunol 3, 852–858 (2002). https://doi.org/10.1038/ni832

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni832

This article is cited by

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