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:

T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells

Abstract

Several gene-deficiency models promote the development of innate CD8+ T cells that have diverse T cell antigen receptors (TCRs) but have a memory phenotype and rapidly produce cytokines. We demonstrate here that similar cells developed in mice deficient in the transcription factor KLF2. However, this was not due to intrinsic deficiency in KLF2 but instead was due to interleukin 4 (IL-4) produced by an expanded population of T cells expressing the transcription factor PLZF. The development of innate CD8+ T cells in mice deficient in the tyrosine kinase Itk and coactivator CBP was also attributable to this IL-4-dependent mechanism. Finally, we show that the same mechanism drove the differentiation of innate CD8+ T cells in BALB/c mice. Our findings identify a previously unknown mechanism of regulation of CD8+ T cells via the production of IL-4 by PLZF+ T cells.

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

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

Figure 1: KLF2-deficient T cells induce a memory-like phenotype on bystander CD8+ thymocytes.
Figure 2: Bystander CD8+ cells have greater in vivo function.
Figure 3: KLF2 deficiency leads to population expansion of PLZF-expressing T cells.
Figure 4: PLZF+ cells are responsible for excess IL-4 production and CD8+ bystander cell effects in KLF2-deficient mice.
Figure 5: Itk−/− mice have a cell-extrinsic CD8+ phenotype and an expanded PLZF+ population.
Figure 6: The memory-like CD8+ phenotype in Itk−/− mice is dependent on IL-4 and PLZF.
Figure 7: Expanded PLZF+ population and an IL-4- and NKT cell–dependent memory-like population in BALB/c mice.

Similar content being viewed by others

References

  1. Williams, M.A. & Bevan, M.J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Bendelac, A., Savage, P.B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Treiner, E. & Lantz, O. CD1d- and MR1-restricted invariant T cells: of mice and men. Curr. Opin. Immunol. 18, 519–526 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Matsuda, J.L., Mallevaey, T., Scott-Browne, J. & Gapin, L. CD1d-restricted iNKT cells, the 'Swiss-Army knife' of the immune system. Curr. Opin. Immunol. 20, 358–368 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kovalovsky, D. et al. The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nat. Immunol. 9, 1055–1064 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Savage, A.K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kuo, C.T., Veselits, M.L. & Leiden, J.M. LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. Science 277, 1986–1990 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Carlson, C.M. et al. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442, 299–302 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Bai, A., Hu, H., Yeung, M. & Chen, J. Kruppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription. J. Immunol. 178, 7632–7639 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Sebzda, E., Zou, Z., Lee, J.S., Wang, T. & Kahn, M.L. Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat. Immunol. 9, 292–300 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Weinreich, M.A. et al. KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors. Immunity 31, 122–130 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Qin, S. et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J. Clin. Invest. 101, 746–754 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Intlekofer, A.M. et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6, 1236–1244 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Intlekofer, A.M. et al. Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321, 408–411 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lewis, D.B. et al. Interleukin 4 expressed in situ selectively alters thymocyte development. J. Exp. Med. 173, 89–100 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Berg, R.E., Crossley, E., Murray, S. & Forman, J. Memory CD8+ T cells provide innate immune protection against Listeria monocytogenes in the absence of cognate antigen. J. Exp. Med. 198, 1583–1593 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kreslavsky, T. et al. TCR-inducible PLZF transcription factor required for innate phenotype of a subset of γδ T cells with restricted TCR diversity. Proc. Natl. Acad. Sci. USA 106, 12453–12458 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Felices, M., Yin, C.C., Kosaka, Y., Kang, J. & Berg, L.J. Tec kinase Itk in γδT cells is pivotal for controlling IgE production in vivo. Proc. Natl. Acad. Sci. USA 106, 8308–8313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Buaas, F.W. et al. Plzf is required in adult male germ cells for stem cell self-renewal. Nat. Genet. 36, 647–652 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Prince, A.L., Yin, C.C., Enos, M.E., Felices, M. & Berg, L.J. The Tec kinases Itk and Rlk regulate conventional versus innate T-cell development. Immunol. Rev. 228, 115–131 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Broussard, C. et al. Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Immunity 25, 93–104 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Atherly, L.O. et al. The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T cells. Immunity 25, 79–91 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Qi, Q. et al. Enhanced development of CD4+ γδ T cells in the absence of Itk results in elevated IgE production. Blood 114, 564–571 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gadue, P. & Stein, P.L.N.K. T cell precursors exhibit differential cytokine regulation and require Itk for efficient maturation. J. Immunol. 169, 2397–2406 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Au-Yeung, B.B. & Fowell, D.J. A key role for Itk in both IFN γ and IL-4 production by NKT cells. J. Immunol. 179, 111–119 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Fukuyama, T. et al. Histone acetyltransferase CBP is vital to demarcate conventional and innate CD8+ T-cell development. Mol. Cell. Biol. 29, 3894–3904 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rymarchyk, S.L. et al. Widespread natural variation in murine natural killer T-cell number and function. Immunology 125, 331–343 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hammond, K.J. et al. CD1d-restricted NKT cells: an interstrain comparison. J. Immunol. 167, 1164–1173 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Azuara, V., Grigoriadou, K., Lembezat, M.P., Nagler-Anderson, C. & Pereira, P. Strain-specific TCR repertoire selection of IL-4-producing Thy-1 dull γδ thymocytes. Eur. J. Immunol. 31, 205–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Readinger, J.A., Mueller, K.L., Venegas, A.M., Horai, R. & Schwartzberg, P.L. Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk. Immunol. Rev. 228, 93–114 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lauritsen, J.P. et al. Marked induction of the helix-loop-helix protein Id3 promotes the γδ T cell fate and renders their functional maturation Notch independent. Immunity 31, 565–575 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ueda-Hayakawa, I., Mahlios, J. & Zhuang, Y. Id3 restricts the developmental potential of γδ lineage during thymopoiesis. J. Immunol. 182, 5306–5316 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Verykokakis, M. et al. Inhibitor of DNA binding 3 limits development of murine slam-associated adaptor protein-dependent 'innate' γδ T cells. PLoS One 5, e9303 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Alonzo, E.S. et al. Development of promyelocytic zinc finger and ThPOK-expressing innate γδ T cells is controlled by strength of TCR signaling and Id3. J. Immunol. 184, 1268–1279 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Allende, M.L. et al. S1P1 receptor expression regulates emergence of NKT cells in peripheral tissues. FASEB J. 22, 307–315 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Raberger, J. et al. The transcriptional regulator PLZF induces the development of CD44 high memory phenotype T cells. Proc. Natl. Acad. Sci. USA 105, 17919–17924 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cerundolo, V., Silk, J.D., Masri, S.H. & Salio, M. Harnessing invariant NKT cells in vaccination strategies. Nat. Rev. Immunol. 9, 28–38 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Morris, S.C. et al. Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation. J. Immunol. 182, 1429–1438 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. 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  PubMed  PubMed Central  Google Scholar 

  41. Ueda, N. et al. CD1d-restricted NKT cell activation enhanced homeostatic proliferation of CD8+ T cells in a manner dependent on IL-4. Int. Immunol. 18, 1397–1404 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Lee, Y.J., Jung, K.C. & Park, S.H. MHC class II-dependent T-T interactions create a diverse, functional and immunoregulatory reaction circle. Immunol. Cell Biol. 87, 65–71 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Lee, Y.J. et al. Generation of PLZF+ CD4+ T cells via MHC class II-dependent thymocyte-thymocyte interaction is a physiological process in humans. J. Exp. Med. 207, 237–246 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Huck, K. et al. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J. Clin. Invest. 119, 1350–1358 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vesosky, B., Rottinghaus, E.K., Davis, C. & Turner, J. CD8+ T Cells in old mice contribute to the innate immune response to Mycobacterium tuberculosis via interleukin-12p70-dependent and antigen-independent production of γ interferon. Infect. Immun. 77, 3355–3363 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dhanji, S., Chow, M.T. & Teh, H.S. Self-antigen maintains the innate antibacterial function of self-specific CD8+ T cells in vivo. J. Immunol. 177, 138–146 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Haque, A. et al. Role of T cells in innate and adaptive immunity against murine Burkholderia pseudomallei infection. J. Infect. Dis. 193, 370–379 (2006).

    Article  PubMed  Google Scholar 

  48. Berg, R.E., Crossley, E., Murray, S. & Forman, J. Relative contributions of NK and CD8+ T cells to IFN-γ mediated innate immune protection against Listeria monocytogenes. J. Immunol. 175, 1751–1757 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank F. Finkelman (University of Cincinnati) for B6 Il4ra−/− mice; D. Kioussis (National Institute for Medical Research, London) for Vav-Cre mice; J. Lingrel (University of Cincinnati) for Klf2fl/fl mice; R. Proia (National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health) for S1pr1fl/fl mice; Y. Shimizu (University of Minnesota) for Itk−/− mice; R. Braun (Jackson Laboratory) for PLZFlu/lu mice; D. Masopust (University of Minnesota) for SMARTA TCR-transgenic mice; P. Brindle (St. Jude Children's Research Hospital) for Cbpfl/flLck-Cre bone marrow; X. Ding, J. Vevea, J. Reyes and C. Mora-Solano for technical assistance; and L. Berg and P. Schwartzberg for discussions. H. O'Donnell did initial experiments with Il4ra−/− mice. Supported by the US National Institutes of Health (R01 AI35296 to K.A.H., R37 AI38903 to S.C.J., and T32 AI007313 to M.A.W.) and the University of Minnesota (M.A.W.).

Author information

Authors and Affiliations

Authors

Contributions

M.A.W. designed and did experiments, analyzed data and wrote the manuscript; O.A.O. did analysis that inspired the direction of this research and provided input on interpretation; S.C.J. provided input to the research design and interpretation; and K.A.H. conceptualized the research, directed the study, analyzed data and edited the manuscript.

Corresponding author

Correspondence to Kristin A Hogquist.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 1062 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weinreich, M., Odumade, O., Jameson, S. et al. T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nat Immunol 11, 709–716 (2010). https://doi.org/10.1038/ni.1898

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1898

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