Journal of Clinical Immunology

, Volume 21, Issue 2, pp 116–125 | Cite as

IL-12 as Well as IL-2 Upregulates CCR5 Expression on T Cell Receptor-Triggered Human CD4+ and CD8+ T Cells

  • Yi-Fu Yang
  • Michio Tomura
  • Masayuki Iwasaki
  • Takao Mukai
  • Ping Gao
  • Shiro Ono
  • Jian-Ping Zou
  • Gene M. Shearer
  • Hiromi Fujiwara
  • Toshiyuki Hamaoka


The expression of chemokine receptors on leukocytes is related to their activation state. However, the exact mechanism underlying the induction of each chemokine receptor is poorly understood. Here, we investigated how CCR5, a chemokine receptor implicated in T cell trafficking and HIV infection, is induced in human T cells. CCR5 was marginally detected on a freshly prepared human peripheral blood mononuclear cell (PBMC) population. Long-term (8-day) stimulation of PBMC with IL-2 resulted in high levels of CCR5 expression on T cells. IL-12 failed to induce CCR5 on T cells in such a directly stimulated PBMC population. Stimulation of PBMC T cells with anti-CD3 plus anti-CD28 induced detectable albeit very low levels of CCR5 along with the induction of IL-12 receptor. However, these TCR-triggered T cells expressed much higher levels of CCR5 when stimulated with IL-12. Although IL-2 also induced CCR5 expression, CCR5 expression was more potent in IL-12 than IL-2 stimulation. These results indicate that, in addition to IL-2, IL-12 plays an important role in the induction of CCR5 expression on T cells, particularly TCR-triggered T cells.

IL-12 IL-2 chemokine receptor CCR5 T cells 


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  1. 1.
    Baggiolini M, Dewald B, Moser B: Human chemokines: An update. Annu Rev Immunol 15:675–705, 1997Google Scholar
  2. 2.
    Rollins BJ: Chemokines. Blood 90:909 -928, 1997Google Scholar
  3. 3.
    Murphy PM: The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol 12:593–633, 1994Google Scholar
  4. 4.
    Springer TA: Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol 57:827–872, 1995Google Scholar
  5. 5.
    Adams DH, Lloyd AR: Chemokines: Leucocyte recruitment and activation cytokines. Lancet 349:490–495, 1997Google Scholar
  6. 6.
    Feng Y, Broder CC, Kennedy PE, Berger EA: HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272:872–877, 1996Google Scholar
  7. 7.
    Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J: The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85:1135–1148, 1996Google Scholar
  8. 8.
    Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di-Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR: Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661–666, 1996Google Scholar
  9. 9.
    Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Peiper SC, Parmentier M, Collman RG, Doms RW: A dual-tropic primary HIV-1 isolate that uses fusin and the β-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 85:1149–1158, 1996Google Scholar
  10. 10.
    Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA: HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381:667–673, 1996Google Scholar
  11. 11.
    Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA: CC CKR5: A RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272:1955–1958, 1996Google Scholar
  12. 12.
    Premack BA, Schall TJ: Chemokine receptors: Gateways to inflammation and infection. Nat Med 2:1174–1178, 1996Google Scholar
  13. 13.
    Tanaka Y, Adams DH, Hubscher S, Hirano H, Siebenlist U, Shaw S: T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1β. Nature 361:79–82, 1993Google Scholar
  14. 14.
    Taub DD, Conlon K, Lloyd AR, Oppenheim JJ, Kelvin DJ: Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1α and MIP-1β. Science 260:355–358, 1993Google Scholar
  15. 15.
    Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM: CCR5 is characteristic of Th1 lymphocytes. Nature 391:344–345, 1998Google Scholar
  16. 16.
    Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR: The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101:746–754, 1998Google Scholar
  17. 17.
    Loetscher P, Seitz M, Baggiolini M, Moser B: Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes. J Exp Med 184:569–577, 1996Google Scholar
  18. 18.
    Wang J, Guan E, Roderiquez G, Norcross MA: Inhibition of CCR5 expression by IL-12 through induction of β-chemokines in human T lymphocytes. J Immunol 163:5763–5769, 1999Google Scholar
  19. 19.
    Ogawa M, Tsutsui T, Zou JP, Mu J, Wijesuriya R, Yu WG, Herrmann S, Kubo T, Fujiwara H, Hamaoka T: Enhanced induction of very late antigen 4/lymphocyte function-associated antigen 1–dependent T-cell migration to tumor sites following administration of interleukin 12. Cancer Res 57:2216–2222, 1997Google Scholar
  20. 20.
    Ogawa M, Umehara K, Yu WG, Uekusa Y, Nakajima C, Tsujimura T, Kubo T, Fujiwara H, Hamaoka T: A critical role for a peritumoral stromal reaction in the induction of T-cell migration responsible for interleukin-12–induced tumor regression. Cancer Res 59:1531–1538, 1999Google Scholar
  21. 21.
    Fujiwara H, Clark SC, Hamaoka T: Cellular and molecular mechanisms underlying IL-12–induced tumor regression. Ann NY Acad Sci 795:294–309, 1996Google Scholar
  22. 22.
    Bleul CC, Wu L, Hoxie JA, Springer TA, Mackay CR: The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci USA 94:1925–1930, 1997Google Scholar
  23. 23.
    Ward SG, Bacon K, Westwick J: Chemokines and T lymphocytes: more than an attraction. Immunity 9:1–11, 1998Google Scholar
  24. 24.
    Zella D, Barabitskaja O, Burns JM, Romerio F, Dunn DE, Revello MG, Gerna G, Reitz M Jr., Gallo RC, Weichold FF: Interferon-γ increases expression of chemokine receptors CCR1, CCR3, and CCR5, but not CXCR4 in monocytoid U937 cells. Blood 91:4444–4450, 1998Google Scholar
  25. 25.
    Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F: Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med 185:825–831, 1997Google Scholar
  26. 26.
    Szabo SJ, Dighe AS, Gubler U, Murphy KM: Regulation of the interleukin (IL)-12R β2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med 185:817–824, 1997Google Scholar
  27. 27.
    Igarashi O, Yamane H, Imajoh-Ohmi S, Nariuchi H: IL-12 receptor (IL-12R) expression and accumulation of IL-12R β 1 and IL-12R β2 mRNAs in CD4+ T cells by costimulation with B7–2 molecules. J Immunol 160:1638–1646, 1998Google Scholar
  28. 28.
    Tomura M, Maruo S, Mu J, Zhou XY, Ahn HJ, Hamaoka T, Okamura H, Nakanishi K, Clark S, Kurimoto M, Fujiwara H: Differential capacities of CD4+, CD8+, and CD4-CD8- T cell subsets to express IL-18 receptor and produce IFN-γ in response to IL-18. J Immunol 160:3759–3765, 1998Google Scholar
  29. 29.
    Wu CY, Demeure C, Kiniwa M, Gately M, Delespesse G: IL-12 induces the production of IFN-γ by neonatal human CD4 T cells. J Immunol 151:1938–1949, 1993Google Scholar
  30. 30.
    Smith KA, Cantrell DA: Interleukin 2 regulates its own receptors. Proc Natl Acad Sci USA 82:864–968, 1985Google Scholar
  31. 31.
    Naume B, Gately M, Espevik T: A comparative study of IL-12 (cytotoxic lymphocyte maturation factor)-, IL-2–, and IL-7–induced effects on immunomagnetically purified CD56+ NK cells. J Immunol 148:2429 -2436, 1992Google Scholar
  32. 32.
    Yanagida T, Kato T, Igarashi O, Inoue T, Nariuchi H: Second signal activity of IL-12 on the proliferation and IL-2R expression of T helper cell-1 clone. J Immunol 152:4919–4928, 1994Google Scholar
  33. 33.
    Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G: Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 170:827–845, 1989Google Scholar
  34. 34.
    Trinchieri G: Interleukin-12: A cytokine produced by antigenpresenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 84: 4008–4027, 1994Google Scholar
  35. 35.
    Cho SS, Bacon CM, Sudarshan C, Rees RC, Finbloom D, Pine R, O'shea JJ: Activation of STAT4 by IL-12 and IFN-α: Evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. J Immunol 157:4781–4789, 1996Google Scholar
  36. 36.
    Rogge L, D'Ambrosio D, Biffi M, Penna G, Minetti LJ, Presky DH, Adorini L, Sinigaglia F: The role of Stat4 in species-specific regulation of Th cell development by type I IFNs. J Immunol 161:6567–6574, 1998Google Scholar
  37. 37.
    Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell J Jr, Murphy KM: Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med 181:1755–1762, 1995Google Scholar
  38. 38.
    Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O'shea JJ, Johnston JA: Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: Differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med 181:399–404, 1995Google Scholar
  39. 39.
    Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P: Identification of RANTES, MIP-1α, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:1811–1815, 1995Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Yi-Fu Yang
    • 1
  • Michio Tomura
    • 1
  • Masayuki Iwasaki
    • 1
  • Takao Mukai
    • 1
  • Ping Gao
    • 1
  • Shiro Ono
    • 1
  • Jian-Ping Zou
    • 2
  • Gene M. Shearer
    • 2
  • Hiromi Fujiwara
    • 1
  • Toshiyuki Hamaoka
    • 1
  1. 1.Department of Oncology (C6), Biomedical Research CenterOsaka University Graduate School of MedicineOsakaJapan
  2. 2.Experimental Immunology Branch, National Cancer InstituteNational Institutes of HealthBethesda

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