Human thymic stromal lymphopoietin promotes dendritic cell–mediated CD4+ T cell homeostatic expansion

Abstract

T cell homeostasis is a self-regulating process for maintaining the size of the peripheral T cell pool. Although dendritic cells (DCs) seem to be important in T cell homeostasis, the molecular regulation of DC-mediated T cell homeostasis is unknown. We show that human DCs activated by thymic stromal lymphopoietin (TSLP) induced a robust expansion of autologous CD4+ T cell populations, which depended on self peptide–major histocompatibility complex. The proliferating T cells adopted and maintained a central memory polyclonal phenotype and could differentiate into T helper type 1 or type 2 effector cells. These results, together with findings of TSLP expression in epithelial cells of mucosal lymphoid tissues and thymus, indicate that TSLP is involved in DC-mediated CD4+ T cell homeostasis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Naive CD4+ T cell proliferation and population expansion with autologous DCs activated by TSLP and other activators.
Figure 2: Cell surface markers characteristic of the CD4+ T cell population expanded by autologous TSLP-DCs.
Figure 3: Cytokine-producing capacity and responsiveness to TCR stimulation of CD4+ T cell populations expanded by autologous TSLP-DCs.
Figure 4: Central and effector memory CD4+ T cell proliferation and population expansion with autologous TSLP-DCs or Med-DCs.
Figure 5: Required factors and clonality of the CD4+ T cell population expanded by autologous TSLP-DCs.
Figure 6: T cell–DC interaction and DC survival.
Figure 7: Expression of human TSLP by cryptic epithelial cells of the tonsil and thymic epithelial cells of Hassal's corpuscles in the thymus.

References

  1. 1

    Jameson, S.C. Maintaining the norm: T-cell homeostasis. Nat. Rev. Immunol. 2, 547–556 (2002).

  2. 2

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

  3. 3

    Grossman, Z., Meier-Schellersheim, M., Sousa, A.E., Victorino, R.M.M. & Paul, W.E. CD4+ T-cell depletion in HIV infection: Are we closer to understanding the cause? Nat. Med. 8, 319–323 (2002).

  4. 4

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

  5. 5

    Goldrath, A.W. Maintaining the status quo: T-cell homeostasis. Microbes Infect. 4, 539–545 (2002).

  6. 6

    Prlic, M., Lefrancois, L. & Jameson, S.C. Multiple choices: regulation of memory CD8 T cell generation and homeostasis by interleukin (IL)-7 and IL-15. J. Exp. Med. 195, F49–52 (2002).

  7. 7

    Sprent, J. & Surh, C.D. Cytokines and T cell homeostasis. Immunol. Lett. 85, 145–149 (2003).

  8. 8

    Seddon, B., Tomlinson, P. & Zamoyska, R. Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat. Immunol. 4, 680–686 (2000).

  9. 9

    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).

  10. 10

    Geginat, J., Sallusto, F. & Lanzavecchia, A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4+ T cells. J. Exp. Med. 194, 1711–1719 (2001).

  11. 11

    Reche, P.A. et al. Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. J. Immunol. 167, 336–343 (2001).

  12. 12

    Soumelis, V. et al. Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680 (2002).

  13. 13

    Ge, Q., Palliser, D., Eisen, H.N. & Chen, J. Homeostatic T cell proliferation in a T cell-dendritic cell coculture system. Proc. Natl. Acad. Sci. USA 99, 2983–2988 (2002).

  14. 14

    Soares, M.V.D. et al. IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire. J. Immunol. 161, 5909–5917 (1998).

  15. 15

    Hassan, J. & Reen, D.J. IL-7 promotes the survival and maturation but not differentiation of human post-thymic CD4+ T cells. Eur. J. Immunol. 28, 3057–3065 (1998).

  16. 16

    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).

  17. 17

    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, 367–374 (1999).

  18. 18

    Oehen, S. & Brduscha-Reim, 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).

  19. 19

    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).

  20. 20

    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).

  21. 21

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

  22. 22

    Piliero, L.M., Sanford, A.N., McDonald-McGinn, D.M., Zackai, E.H. & Sullivan, K.E. T cell homeostasis in human with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood 103, 1020–1025 (2004).

  23. 23

    Kunkel, E.J. & Butcher, E.C. Chemokines and the tissue-specific migration of lymphocytes. Immunity 16, 1–4 (2002).

  24. 24

    Messi, M. et al. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nat. Immunol. 4, 78–86 (2002).

  25. 25

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

  26. 26

    Anderson, M.S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).

  27. 27

    Pitkanen, J. & Peterson, P. Autoimmune regulator: from loss of function to immunity. Genes Immun. 4, 12–21 (2003).

  28. 28

    Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C.C. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350–354 (2003).

  29. 29

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

  30. 30

    Ferreira, C., Barthlott, T., Garcia, S., Zamoyska, R. & Stockinger, B. Differential survival of naive CD4 and CD8 T cells. J. Immunol. 165, 3689–3694 (2000).

  31. 31

    Muranski, P., Chmielwoski, 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).

  32. 32

    Marrack, P. & Kappler, J. The staphylococcal enterotoxins and their relatives. Science 248, 705–711 (1990).

  33. 33

    Geginat, J., Lanzavecchia, A. & Sallusto, F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 101, 4260–4266 (2003).

  34. 34

    Miller, R.A. & Stutman, O. T cell repopulation from functionally restricted splenic progenitors: 10,000-fold expansion documented by using limiting dilution analyses. J. Immunol. 133, 2925–2932 (1984).

  35. 35

    Bell, E.B., Sparshott, S.M., Drayson, M.T. & Ford, W.L. The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature T cells. J. Immunol. 139, 1379–1384 (1987).

  36. 36

    Rocha, B., Dautigny, N. & Pereira, P. Peripheral T lymphocytes: expansion potential and homeostatic regulation of pool sizes and CD4/CD8 ratios in vivo . Eur. J. Immunol. 19, 905–911 (1989).

  37. 37

    Sprent, J., Schaefer, M., Hurd, M., Surh, C.D. & Ron, Y. Mature murine B and T cells transferred to SCID mice can survive indefinitely and many maintain a virgin phenotype. J. Exp. Med. 174, 717–728 (1991).

  38. 38

    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).

  39. 39

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

  40. 40

    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).

  41. 41

    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).

  42. 42

    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).

  43. 43

    Polic, B., Kunkel, D., Scheffold, A. & Rajewsky, K. How αβ T cells deal with induced TCRα ablation. Proc. Natl. Acad. Sci. USA 98, 8744–8749 (2001).

  44. 44

    Nussenzweig, M.C. & Steinman, R.M. Contribution of dendritic cells to stimulation of the murine syngeneic mixed leukocyte reaction. J. Exp. Med. 151, 1196–1212 (1980).

  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

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

  47. 47

    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).

  48. 48

    Leonard, W.J. TSLP: finally in the limelight. Nat. Immunol. 3, 605–607 (2002).

  49. 49

    Quentmeier, H. et al. Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia 15, 1286–1292 (2001).

  50. 50

    Lyons, A.B. & Parish, C.R. Determination of lymphocyte division by flow cytometry. J. Immunol. Methods. 171, 131–137 (1994).

  51. 51

    D'Andrea, A. et al. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J. Exp. Med. 176, 1387–1398 (1992).

Download references

Acknowledgements

We thank B. Desai, S. Jungers, J. Shoemaker and J. Cupp for cell sorting; D. Wylie for assistance in preparation of the manuscript; and L.L. Lanier, J. Chen, B. Su, S. Ullrich, M.F. Wilkinson and Y.-H. Wang for critical reading and suggestions. DNAX Research Institute is supported by Schering-Plough.

Author information

Correspondence to Yong-Jun Liu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Further reading