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:

CD4+ T cell survival is not directly linked to self-MHC–induced TCR signaling

Nature Immunology volume 1, pages 329–335 (2000)Cite this article

Abstract

T cell receptor (TCR) signaling triggered by recognition of self-major histocompatibility complex (MHC) ligands has been proposed to maintain the viability of naïve T cells and to provoke their proliferation in T cell–deficient hosts. Consistent with this, the partially phosphorylated state of TCRζ chains in naïve CD4+ and CD8+ T cells in vivo was found to be actively maintained by TCR interactions with specific peptide-containing MHC molecules. TCR ligand-dependent phosphorylation of TCRζ was lost within one day of cell transfer into MHC-deficient hosts, yet the survival of transferred CD4+ lymphocytes was the same in recipients with or without MHC class II expression for one month. Thus, despite clear evidence for TCR signaling in nonactivated naïve T cells, these data argue against the concept that such signaling plays a predominant role in determining lymphocyte lifespan.

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: Analysis of naïve TCRζ (ζ here and in all figures) chain phosphorylation.
Figure 2: Maintenance of phosphorylated TCRζ in CD4+ T cells requires MHC class II and specific peptides.
Figure 3: Maintenance of phosphorylated TCRζ in naïve CD4+ T cells requires CD4–MHC class II interactions.
Figure 4: Maintenance of phosphorylated TCRζ in naïve CD8+ T cells depends on MHC class I.
Figure 5: Survival of CD4+ T cells one month after transfer.

Similar content being viewed by others

References

  1. Pircher, H., Rohrer, U. H., Moskophidis, D., Zinkernagel, R. M. & Hengartner, H. Lower receptor avidity required for thymic clonal deletion than for effector T-cell function. Nature 351, 482–485 (1991).

    Article  CAS  Google Scholar 

  2. Smyth, L. A. et al. Altered peptide ligands induce quantitatively but not qualitatively different intracellular signals in primary thymocytes. Proc. Natl Acad. Sci. USA 95, 8193–8198 (1998).

    Article  CAS  Google Scholar 

  3. Davey, G. M. et al. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867–1874 (1998).

    Article  CAS  Google Scholar 

  4. Lucas, B., Štefanová, I., Yasutomo, K., Dautigny, N. & Germain, R. N. Divergent changes in the sensitivity of maturing T cells to structurally related ligands underlies formation of a useful T cell repertoire. Immunity 10, 367–376 (1999).

    Article  CAS  Google Scholar 

  5. Peterson, D. A., DiPaolo, R. J., Kanagawa, O. & Unanue, E. R. Negative selection of immature thymocytes by a few peptide-MHC complexes: differential sensitivity of immature and mature T cells. J. Immunol. 162, 3117–3120 (1999).

    CAS  Google Scholar 

  6. Takeda, S., Rodewald, H. R., Arakawa, H., Bluethmann, H. & Shimizu, T. MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life span. Immunity 5, 217–228 (1996).

    Article  CAS  Google Scholar 

  7. Tanchot, C., Lemonnier, F. A., Perarnau, B., Freitas, A. A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057–2062 (1997).

    Article  CAS  Google Scholar 

  8. Rooke, R., Waltzinger, C., Benoist, C. & Mathis, D. Targeted complementation of MHC class II deficiency by intrathymic delivery of recombinant adenoviruses. Immunity 7, 123–134 (1997).

    Article  CAS  Google Scholar 

  9. Brocker, T. Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells. J. Exp. Med. 186, 1223–1232 (1997).

    Article  CAS  Google Scholar 

  10. Kirberg, J., Berns, A. & von Boehmer, H. Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules. J. Exp. Med. 186, 1269–1275 (1997).

    Article  CAS  Google Scholar 

  11. Markiewicz, M.A. et al. Long-term T cell memory requires the surface expression of self-peptide/major histocompatibility complex molecules. Proc. Natl Acad. Sci. USA 95, 3065–3070 (1998).

    Article  CAS  Google Scholar 

  12. Viret, C., Wong, F. S. & Janeway, C. A. Jr. Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition. Immunity 10, 559–568 (1999).

    Article  CAS  Google Scholar 

  13. Witherden, D. et al. Tetracycline-controllable selection of CD4+ T cells. Half-life and survival signals in the absence of major histocompatibility complex class II molecules. J. Exp. Med. 191, 355–364 (2000).

    Article  CAS  Google Scholar 

  14. Beutner, U. & MacDonald, H. R. TCR-MHC class II interaction is required for peripheral expansion of CD4 cells in a T cell-deficient host. Int. Immunol. 10, 305–310 (1998).

    Article  CAS  Google Scholar 

  15. Oehen, S. & Brduscha-Riem, K. Naive cytotoxic T lymphocytes spontaneously acquire effector function in lymphocytopenic recipients: a pitfall for T cell memory studies? Eur. J. Immunol. 29, 608–614 (1999).

    Article  CAS  Google Scholar 

  16. Bender, J., Mitchell, T., Kappler, J. & Marrack, P. CD4+ T cell division in irradiated mice requires peptides distinct from those responsible for thymic selection. J. Exp. Med. 190, 367–373 (1999).

    Article  CAS  Google Scholar 

  17. 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 

  18. Goldrath, A. W. & Bevan, M. J. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 (1999).

    Article  CAS  Google Scholar 

  19. Kieper, W. C. & Jameson, S. C. Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide/MHC ligands. Proc. Natl Acad. Sci. USA 96, 13306–13311 (1999).

    Article  CAS  Google Scholar 

  20. 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 

  21. Muranski, P., Chmielowski, B. & Ignatowicz, L. Mature CD4+ T cells perceive a positively selecting class II MHC/peptide complex in the periphery. J. Immunol. 164, 3087–3094 (2000).

    Article  CAS  Google Scholar 

  22. van Oers, N. S. et al. Constitutive tyrosine phosphorylation of the T-cell receptor (TCR) ζ subunit: regulation of TCR-associated protein tyrosine kinase activity by TCR ζ. Mol. Cell. Biol. 13, 5771–5780 (1993).

    Article  CAS  Google Scholar 

  23. van Oers, N.S., Killeen, N. & Weiss, A. ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR ζ in murine thymocytes and lymph node T cells. Immunity 1, 675–685 (1994).

    Article  CAS  Google Scholar 

  24. Sloan-Lancaster, J., Shaw, A. S., Rothbard, J. B. & Allen, P. M. Partial T cell signaling: altered phospho-ζ and lack of Zap70 recruitment in APL-induced T cell anergy. Cell 79, 913–922 (1994).

    Article  CAS  Google Scholar 

  25. Madrenas, J. et al. phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 267, 515–518 (1995).

    Article  CAS  Google Scholar 

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

  27. Rocha, B. & von Boehmer, H. Peripheral selection of the T cell repertoire. Science 251, 1225–1228 (1991).

    Article  CAS  Google Scholar 

  28. Saparov, A. et al. Memory/effector T cells in TCR transgenic mice develop via recognition of enteric antigens by a second, endogenous TCR. Int. Immunol. 11, 1253–1264 (1999).

    Article  CAS  Google Scholar 

  29. Ardouin, L. et al. Crippling of CD3-ζ ITAMs does not impair T cell receptor signaling. Immunity 10, 409–420 (1999).

    Article  CAS  Google Scholar 

  30. Shores, E. W. et al. Role of the multiple T cell receptor (TCR)-ζ chain signaling motifs in selection of the T cell repertoire. J. Exp. Med. 185, 893–900 (1997).

    Article  CAS  Google Scholar 

  31. Mackall, C. L., Hakim, F. T. & Gress, R. E. Restoration of T-cell homeostasis after T-cell depletion. Semin. Immunol. 9, 339–346 (1997).

    Article  CAS  Google Scholar 

  32. Wilkinson, R. W., Anderson, G., Owen, J. J. & Jenkinson, E. J. Positive selection of thymocytes involves sustained interactions with the thymic microenvironment. J. Immunol. 155, 5234–5240 (1995).

    CAS  Google Scholar 

  33. Kisielow, P. & Miazek, A. Positive selection of T cells: rescue from programmed cell death and differentiation require continual engagement of the T cell receptor. J. Exp. Med. 181, 1975–1984 (1995).

    Article  CAS  Google Scholar 

  34. Schmitt, S., Muller, K. P. & Kyewski, B. A. Two separable T cell receptor signals reconstitute positive selection of CD4 lineage T cells in vivo. Eur. J. Immunol. 27, 2139–2144 (1997).

    Article  CAS  Google Scholar 

  35. Yasutomo, K., Lucas, B. & Germain, R. N. TCR signaling for initiation and completion of thymocyte positive selection has distinct requirements for ligand quality and presenting cell type. J. Immunol., in press (2000).

  36. Miyazaki, T. et al. Mice lacking H2-M complexes, enigmatic elements of the MHC class II peptide-loading pathway. Cell 84, 531–541 (1996).

    Article  CAS  Google Scholar 

  37. Martin, W.D. et al. H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection. Cell 84, 543–550 (1996).

    Article  CAS  Google Scholar 

  38. Nakayama, T., Singer, A., Hsi, E. D. & Samelson, L. E. Intrathymic signaling in immature CD4+CD8+ thymocytes results in tyrosine phosphorylation of the T-cell receptor ζ chain. Nature 341, 651–654 (1989).

    Article  CAS  Google Scholar 

  39. Robey, E. & Fowlkes, B. J. Selective events in T cell development. Annu. Rev. Immunol. 12, 675–705 (1994).

    Article  CAS  Google Scholar 

  40. Riberdy, J. M., Mostaghel, E. & Doyle, C. Disruption of the CD4-major histocompatibility complex class II interaction blocks the development of CD4+ T cells in vivo. Proc. Natl Acad. Sci. USA 95, 4493–4498 (1998).

    Article  CAS  Google Scholar 

  41. Mostaghel, E. A., Riberdy, J. M., Steeber, D. A. & Doyle, C. Coreceptor-independent T cell activation in mice expressing MHC class II molecules mutated in the CD4 binding domain. J. Immunol. 161, 6559–6566 (1998).

    CAS  Google Scholar 

  42. König, R., Huang, L. Y. & Germain, R. N. MHC class II interaction with CD4 mediated by a region analogous to the MHC class I binding site for CD8. Nature 356, 796–798 (1992).

    Article  Google Scholar 

  43. Cosgrove, D. et al. Mice lacking MHC class II molecules. Cell 66, 1051–1066 (1991).

    Article  CAS  Google Scholar 

  44. Clarke, S. R. & Rudensky, A. Y. Survival and homeostatic proliferation of naive peripheral CD4+ T cells in the absence of self peptide:MHC complexes. J. Immunol. 165, 2458–2464 (2000).

    Article  CAS  Google Scholar 

  45. Tanchot, C. & Rocha, B. Peripheral selection of T cell repertoires: the role of continuous thymus output. J. Exp. Med. 186, 1099–1106 (1997).

    Article  CAS  Google Scholar 

  46. Pestano, G.A. et al. Inactivation of misselected CD8 T cells by CD8 gene methylation and cell death. Science 284, 1187–1191 (1999).

    Article  CAS  Google Scholar 

  47. Ljunggren, H. G., Van Kaer, L., Ashton-Rickardt, P. G., Tonegawa, S. & Ploegh, H. L. Differential reactivity of residual CD8+ T lymphocytes in TAP1 and β2-microglobulin mutant mice. Eur. J. Immunol. 25, 174–178 (1995).

    Article  CAS  Google Scholar 

  48. Ljunggren, H. G., Glas, R., Sandberg, J. K. & Kärre, K. Reactivity and specificity of CD8+ T cells in mice with defects in the MHC class I antigen-presenting pathway. Immunol. Rev. 151, 123–148 (1996).

    Article  CAS  Google Scholar 

  49. Petricoin, E. F. et al. Antiproliferative action of interferon-α requires components of T- cell-receptor signalling. Nature 390, 629–632 (1997).

    Article  CAS  Google Scholar 

  50. Lee, I. H., Li, W. P., Hisert, K. B. & Ivashkiv, L. B. Inhibition of interleukin 2 signaling and signal transducer and activator of transcription (STAT)5 activation during T cell receptor- mediated feedback inhibition of T cell expansion. J. Exp. Med. 190, 1263–1274 (1999).

    Article  CAS  Google Scholar 

  51. Mary, F. et al. Modulation of TCR signaling by beta1 integrins: role of the tyrosine phosphatase SHP-1. Eur. J. Immunol. 29, 3887–3897 (1999).

    Article  CAS  Google Scholar 

  52. Germain, R. N. & Štefanová, I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467–522 (1999).

    Article  CAS  Google Scholar 

  53. Marrack, P. et al. Homeostasis of αβ TCR+ T cells. Nature Immunol. 1, 107–111 (2000).

    Article  CAS  Google Scholar 

  54. Grossman, Z. & Paul, W. E. Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses. Proc. Natl Acad. Sci. USA 89, 10365–10369 (1992).

    Article  CAS  Google Scholar 

  55. Kersh, B. E., Kersh, G. J. & Allen, P. M. Partially phosphorylated T cell receptor ζ molecules can inhibit T cell activation. J. Exp. Med. 190, 1627–1636 (1999).

    Article  CAS  Google Scholar 

  56. Zijlstra, M. et al. β2-microglobulin deficient mice lack CD4−8+ cytolytic T cells. Nature 344, 742–746 (1990).

    Article  CAS  Google Scholar 

  57. Van Kaer, L., Ashton-Rickardt, P. G., Ploegh, H. L. & Tonegawa, S. TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD4-8+ T cells. Cell 71, 1205–1214 (1992).

    Article  CAS  Google Scholar 

  58. Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    Article  CAS  Google Scholar 

  59. Kaye, J. et al. Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature 341, 746–749 (1989).

    Article  CAS  Google Scholar 

  60. Kisielow, P., Bluthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333, 742–746 (1988).

    Article  CAS  Google Scholar 

  61. Pircher, H., Burki, K., Lang, R., Hengartner, H. & Zinkernagel, R. M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342, 559–561 (1989).

    Article  CAS  Google Scholar 

  62. Seder, R. A., Paul, W. E., Davis, M. M. & Fazekas de St. Groth, B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J. Exp. Med. 176, 1091–1098 (1992).

    Article  CAS  Google Scholar 

  63. Štefanová, I. et al. Lipopolysaccharide induces activation of CD14-associated protein tyrosine kinase p53/56lyn. J. Biol. Chem. 268, 20725–20728 (1993).

    Google Scholar 

  64. Burkhardt, A. L. et al. Temporal regulation of non-transmembrane protein tyrosine kinase enzyme activity following T cell antigen receptor engagement. J. Biol. Chem. 269, 23642–23647 (1994).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Swofford, C. Eigsti and D. Stephany of the NIAID Flow Cytometry Facility for cell sorting; A. Fox for technical assistance; D. Raulet, P. Schwartzberg, P. Love, J. Delon, A. Porgador and C. Broussard for discussions and reading the manuscript; B. Rocha, R. Schwartz, B. J. Fowlkes and members of the Germain lab for helpful discussion; C. Doyle, J. Riberdy, L. Van Kaer and E. Bikoff for mice; J. Bolen, A. Iwasaki and B. Kelsall for reagents; and G. Asfaw, F. Bishop and C. Callahan for assistance with typing mice.

Author information

Author notes

  1. Koji Yasutomo

    Present address: Department of Pediatrics, School of Medicine, University of Tokushima, Kuramoto 3, Tokushima, 770, Japan

  2. Jeffrey R. Dorfman and Irena Štefanová: These authors contributed equally to this work.

Authors and Affiliations

  1. Lymphocyte Biology Section, Laboratory of Immunology, Building 10 Room 11N311

    Ronald N. Germain

  2. National Institutes of Health, Bethesda, 20892, MD, USA

    Ronald N. Germain

Authors
  1. Jeffrey R. Dorfman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irena Štefanová
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koji Yasutomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ronald N. Germain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald N. Germain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dorfman, J., Štefanová, I., Yasutomo, K. et al. CD4+ T cell survival is not directly linked to self-MHC–induced TCR signaling. Nat Immunol 1, 329–335 (2000). https://doi.org/10.1038/79783

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79783

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