Homeostasis of Vα14i NKT cells


CD1d-reactive natural killer T (NKT) cells with an invariant Vα14 rearrangement (Vα14i) are a distinct subset of T lymphocytes that likely have important immune-regulatory functions. Little is known regarding the factors responsible for their peripheral survival. Using α-galactosylceramide–containing CD1d tetramers to detect Vα14i NKT cells, we show here that the expansion of Vα14i NKT cells in lymphopenic mice was not dependent on CD1d expression and was unaffected by the presence of host NKT cells. Additionally, we found that IL-15 was important in the expansion and/or survival of Vα14i NKT cells, with IL-7 playing a lesser role. These results demonstrate that the homeostatic requirements for CD1d-restricted NKT cells, which are CD4+ or CD4CD8, resemble those of CD8+ memory T cells. We propose that this expansion and/or survival in the periphery of Vα14i NKT cells is affected by competition for IL-15, and that IL-15–requiring cells—such as NK cells and CD8+ memory cells—may define the Vα14i NKT cell niche.

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Figure 1: Vα14i T cell proliferation in a lymphopenic environment.
Figure 2: The NKT cell niche and CD1d requirement for proliferation.
Figure 3: Vα14i T cell deficiencies in cytokine-deficient mice.
Figure 4: Analysis of developmental intermediates of Vα14i T cells in cytokine- deficient mice.
Figure 5: Response of Vα14i T cells to IL-15 in vitro and in vivo.
Figure 6: Turnover of peripheral Vα14i T cells in IL-15−/− mice.
Figure 7: Proliferation of Vα14i T cells in cytokine-deficient mice.
Figure 8: Competition of other cell types with Vα14i T cells for IL-15 in vitro and in vivo.


  1. 1

    Tough, D.F. & Sprent, J. Life span of naive and memory T cells. Stem Cells 13, 242–249 (1995).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    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, 49–52 (2002).

    Article  Google Scholar 

  8. 8

    Ma, A., Boone, D.L. & Lodolce, J.P. The pleiotropic functions of interleukin 15: not so interleukin 2-like after all. J. Exp. Med. 191, 753–756 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Kronenberg, M. & Gapin, L. The unconventional lifestyle of NKT cells. Nature Rev. Immunol. 2, 557–568 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Matsuda, J.L. et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192, 741–754 (2000).

    CAS  Article  Google Scholar 

  11. 11

    van der Vliet, H.J. et al. Circulating Vα24+ Vβ11+ NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin. Immunol. 100, 144–148 (2001).

    CAS  Article  Google Scholar 

  12. 12

    Kojo, S., Adachi, Y., Keino, H., Taniguchi, M. & Sumida, T. Dysfunction of T cell receptor AV24AJ18+, BV11+ double-negative regulatory natural killer T cells in autoimmune diseases. Arthritis Rheum. 44, 1127–1138 (2001).

    CAS  Article  Google Scholar 

  13. 13

    Fehniger, T.A. & Caligiuri, M.A. Interleukin 15: biology and relevance to human disease. Blood 97, 14–32 (2001).

    CAS  Article  Google Scholar 

  14. 14

    Husson, H. et al. Functional effects of TNF and lymphotoxin α1β2 on FDC-like cells. Cell. Immunol. 203, 134–143 (2000).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  18. 18

    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).

    CAS  Article  Google Scholar 

  19. 19

    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).

    CAS  Article  Google Scholar 

  20. 20

    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).

    CAS  Article  Google Scholar 

  21. 21

    Zeng, D., Lee, M.K., Tung, J., Brendolan, A. & Strober, S. Cutting edge: a role for CD1 in the pathogenesis of lupus in NZB/NZW mice. J. Immunol. 164, 5000–5004 (2000).

    CAS  Article  Google Scholar 

  22. 22

    Ohteki, T., Ho, S., Suzuki, H., Mak, T.W. & Ohashi, P.S. Role for IL-15/IL-15 receptor β-chain in natural killer 1.1+ T cell receptor-αβ+ cell development. J. Immunol. 159, 5931–5935 (1997).

    CAS  PubMed  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    Lodolce, J.P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Ohteki, T. et al. The transcription factor interferon regulatory factor 1 (IRF-1) is important during the maturation of natural killer 1.1+ T cell receptor-α/β+ (NK1+T) cells, natural killer cells, and intestinal intraepithelial T cells. J. Exp. Med. 187, 967–972 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Walunas, T.L., Wang, B., Wang, C.R. & Leiden, J.M. Cutting edge: the Ets1 transcription factor is required for the development of NK T cells in mice. J. Immunol. 164, 2857–2860 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Vicari, A.P. et al. NK1.1+ T cells from IL-7-deficient mice have a normal distribution and selection but exhibit impaired cytokine production. Int. Immunol. 8, 1759–1766 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Gapin, L., Matsuda, J.L., Surh, C.D. & Kronenberg, M. NKT cells derive from double-positive thymocytes that are positively selected by CD1d. Nature Immunol. 2, 971–978 (2001).

    CAS  Article  Google Scholar 

  29. 29

    Pellicci, D.G. et al. NKT cells develop through a thymus-dependent NK1.1CD4+ CD1d-dependent precursor stage. J. Exp. Med. 195, 835–844 (2002).

    CAS  Article  Google Scholar 

  30. 30

    Benlagha, K., Kyin, T., Beavis, A., Teyton, L. & Bendelac, A. A thymic precursor to the NKT cell lineage. Science 296, 553–555 (2002).

    CAS  Article  Google Scholar 

  31. 31

    Kieper, W.C. et al. Over-expression of IL-7 leads to IL-15 independent generation of memory-phenotype CD8+ T cells. J. Exp. Med. 195, 1533–1539 (2002).

    CAS  Article  Google Scholar 

  32. 32

    Tan, J.T. et al. IL-15 and IL-7 jointly regulate homeostatic proliferation of memory-phenotype CD8+ cells but are not required for memory-phenotype CD4+ cells. J. Exp. Med. 195, 1523–1532 (2002).

    CAS  Article  Google Scholar 

  33. 33

    Mertsching, E., Burdet, C. & Ceredig, R. IL-7 transgenic mice: analysis of the role of IL-7 in the differentiation of thymocytes in vivo and in vitro. Int. Immunol. 7, 401–414 (1995).

    CAS  Article  Google Scholar 

  34. 34

    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).

    CAS  Article  Google Scholar 

  35. 35

    Coles, M.C. & Raulet, D.H. NK1.1+ T cells in the liver arise in the thymus and are selected by interactions with class I molecules on CD4+CD8+ cells. J. Immunol. 164, 2412–2418 (2000).

    CAS  Article  Google Scholar 

  36. 36

    Arase, H., Arase, N. & Saito, T. Interferon γ production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking. J. Exp. Med. 183, 2391–2396 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Eberl, G. & MacDonald, H.R. Rapid death and regeneration of NKT cells in anti-CD3ε- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 9, 345–353 (1998).

    CAS  Article  Google Scholar 

  38. 38

    Hammond, K.J. et al. NKT cells are phenotypically and functionally diverse. Eur. J. Immunol. 29, 3768–3781 (1999).

    CAS  Article  Google Scholar 

  39. 39

    Eberl, G. et al. Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells. J. Immunol. 162, 6410–6419 (1999).

    CAS  PubMed  Google Scholar 

  40. 40

    Carnaud, C. et al. Cutting edge: cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J. Immunol. 163, 4647–4650 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Eberl, G., Brawand, P. & MacDonald, H.R. Selective bystander proliferation of memory CD4+ and CD8+ T cells upon NK T or T cell activation. J. Immunol. 165, 4305–4311 (2000).

    CAS  Article  Google Scholar 

  42. 42

    Kim, S., Iizuka, K., Aguila, H.L., Weissman, I.L. & Yokoyama, W.M. In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc. Natl. Acad. Sci. USA 97, 2731–2736 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Becker, T.C. et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 195, 1541–1548 (2002).

    CAS  Article  Google Scholar 

  44. 44

    Goldrath, A.W. et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med. 195, 1515–1522 (2002).

    CAS  Article  Google Scholar 

  45. 45

    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).

    CAS  Article  Google Scholar 

  46. 46

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

    CAS  Article  Google Scholar 

  47. 47

    Kawakami, K. et al. Monocyte chemoattractant protein-1-dependent increase of Vα14 NKT cells in lungs and their roles in Th1 response and host defense in cryptococcal infection. J. Immunol. 167, 6525–6532 (2001).

    CAS  Article  Google Scholar 

  48. 48

    Marrack, P., Kappler, J. & Mitchell, T. Type I interferons keep activated T cells alive. J. Exp. Med. 189, 521–529 (1999).

    CAS  Article  Google Scholar 

  49. 49

    Hobbs, J.A. et al. Selective loss of natural killer T cells by apoptosis following infection with lymphocytic choriomeningitis virus. J. Virol. 75, 10746–10754 (2001).

    CAS  Article  Google Scholar 

  50. 50

    Matsuda, J.L. et al. Natural killer T cells reactive to a single glycolipid exhibit a highly diverse T cell receptor β repertoire and small clone size. Proc. Natl. Acad. Sci. USA 98, 12636–12641 (2001).

    CAS  Article  Google Scholar 

  51. 51

    von Freeden-Jeffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).

    CAS  Article  Google Scholar 

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We thank G. Kim and J. Sprent for helpful discussions, H. Cheroutre for critical reading of the manuscript and TSRI for help with cell sorting. Supported by NIH grants CA52511 (to M. K.) and AI45809 (to C. D. S.) and a grant from the Human Frontiers of Science Research Program (to M. K.). L. G. is supported by the Cancer Research Institute, W. C. K. is supported by U.S. Public Health Service Institutional National Research Service Award AI07244, J. T. T. is supported by US Public Health Service Institute National Research Service Award H07196 and C. D. S. is supported by the Leukemia and Lymphoma Society.

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Correspondence to Mitchell Kronenberg.

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Matsuda, J., Gapin, L., Sidobre, S. et al. Homeostasis of Vα14i NKT cells. Nat Immunol 3, 966–974 (2002). https://doi.org/10.1038/ni837

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