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Mast cell–dependent migration of effector CD8+ T cells through production of leukotriene B4

Abstract

Studies in both humans and rodents indicate that CD8+ T cells may be important in allergic inflammation. However, neither the mechanisms that mediate CD8+ T cell recruitment to inflamed tissues nor the relative participation of effector and central memory CD8+ T cells is known. Here we report that activated mast cells induced chemotaxis of effector, but not central memory, CD8+ T cells through production of leukotriene B4 (LTB4). These studies indicate that LTB4 production by activated peripheral leukocytes could be important for the recruitment of effector CD8+ T cells to sites of inflammation.

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Figure 1: Activated mast cells induce selective migration of TEFF cells.
Figure 2: Mast cell–induced TEFF cell migration is dependent on mast cell production of leukotrienes.
Figure 3: LTB4 induces migration of TEFF cells, but not TCM cells.
Figure 4: LTB4-induced TEFF cell migration is mediated by BLT1.
Figure 5: LTB4-induced TEFF cell migration requires a PTX-sensitive pathway.
Figure 6: Activated CD8+ T cells do not migrate to LTB4.
Figure 7: LTB4 sensitivity is induced by TCR aggregation and culture in IL-2.

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References

  1. Metcalfe, D.D., Baram, D. & Mekori, Y.A. Mast cells. Physiol. Rev. 77, 1033–1079 (1997).

    Article  CAS  Google Scholar 

  2. Benoist, C. & Mathis, D. Mast cells in autoimmune disease. Nature 420, 875–878 (2002).

    Article  CAS  Google Scholar 

  3. Mekori, Y.A. & Metcalfe, D.D. Mast cell-T cell interactions. J. Allergy Clin. Immunol. 104, 517–523 (1999).

    Article  CAS  Google Scholar 

  4. Gonzalez, M.C. et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) T-cells in asthma. Relative increases in OKT8 cells in single early responders compared with those in late-phase responders. Am. Rev. Respir. Dis. 136, 600–604 (1987).

    Article  CAS  Google Scholar 

  5. Haczku, A. et al. T-cells subsets and activation in bronchial mucosa of sensitized Brown-Norway rats after single allergen exposure. Immunology 85, 591–597 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hamelmann, E. et al. Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a murine model of airway sensitization. J. Exp. Med. 183, 1719–1729 (1996).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Weninger, W., Crowley, M.A., Manjunath, N. & von Andrian, U.H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001).

    Article  CAS  Google Scholar 

  10. Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).

    Article  CAS  Google Scholar 

  11. Ott, V.L., Tamir, I., Niki, M., Pandolfi, P.P. & Cambier, J.C. Downstream of kinase, p62dok, is a mediator of FcγIIB inhibition of FcεRI signaling. J. Immunol. 168, 4430–4439 (2002).

    Article  CAS  Google Scholar 

  12. Teague, T.K. et al. Activation changes the spectrum but not the diversity of genes expressed by T cells. Proc. Natl. Acad. Sci. USA 96, 12691–12696 (1999).

    Article  CAS  Google Scholar 

  13. Yokomizo, T., Izumi, T. & Shimizu, T. Leukotriene B4: metabolism and signal transduction. Arch. Biochem. Biophys. 385, 231–241 (2001).

    Article  CAS  Google Scholar 

  14. Dixon, R.A. et al. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 343, 282–284 (1990).

    Article  CAS  Google Scholar 

  15. Tager, A.M. et al. BLTR mediates leukotriene B4-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis. J. Exp. Med. 192, 439–446 (2000).

    Article  CAS  Google Scholar 

  16. Mackarel, A.J., Russell, K.J., Brady, C.S., FitzGerald, M.X. & O'Connor, C.M. Interleukin-8 and leukotriene-B4, but not formylmethionyl leucylphenylalanine, stimulate CD18-independent migration of neutrophils across human pulmonary endothelial cells in vitro. Am. J. Respir. Cell. Mol. Biol. 23, 154–161 (2000).

    Article  CAS  Google Scholar 

  17. Yokomizo, T., Kato, K., Terawaki, K., Izumi, T. & Shimizu, T. A second leukotriene B4 receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J. Exp. Med. 192, 421–432 (2000).

    Article  CAS  Google Scholar 

  18. Koch, K. et al. (+)-1-(3S,4R)-[3-(4-phenylbenzyl)-4-hydroxychroman-7-yl]cyclopentane carboxylic acid, a highly potent, selective leukotriene B4 antagonist with oral activity in the murine collagen-induced arthritis model. J. Med. Chem. 37, 3197–3199 (1994).

    Article  CAS  Google Scholar 

  19. Showell, H.J., Breslow, R., Conklyn, M.J., Hingorani, G.P. & Koch, K. Characterization of the pharmacological profile of the potent LTB4 antagonist CP-105,696 on murine LTB4 receptors in vitro. Br. J. Pharmacol. 117, 1127–1132 (1996).

    Article  CAS  Google Scholar 

  20. Yokomizo, T., Kato, K., Hagiya, H., Izumi, T. & Shimizu, T. Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2. J. Biol. Chem. 276, 12454–12459 (2001).

    Article  CAS  Google Scholar 

  21. Yokomizo, T. et al. Leukotriene B4 receptor. Cloning and intracellular signaling. Am. J. Respir. Crit. Care Med. 161, S51–55 (2000).

    Article  CAS  Google Scholar 

  22. Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y. & Shimizu, T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387, 620–624 (1997).

    Article  CAS  Google Scholar 

  23. Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).

    Article  CAS  Google Scholar 

  24. Freeland, H.S., Schleimer, R.P., Schulman, E.S., Lichtenstein, L.M. & Peters, S.P. Generation of leukotriene B4 by human lung fragments and purified human lung mast cells. Am. Rev. Respir. Dis. 138, 389–394 (1988).

    Article  CAS  Google Scholar 

  25. Katz, H.R. et al. Secretory granule mediator release and generation of oxidative metabolites of arachidonic acid via Fc-IgG receptor bridging in mouse mast cells. J. Immunol. 148, 868–871 (1992).

    CAS  PubMed  Google Scholar 

  26. Sayama, K. et al. Transcriptional response of human mast cells stimulated via the FcεRI and identification of mast cells as a source of IL-11. BMC Immunol. 3, 5 (2002).

    Article  Google Scholar 

  27. Nakajima, T. et al. Marked increase in CC chemokine gene expression in both human and mouse mast cell transcriptomes following Fcε receptor I cross-linking: an interspecies comparison. Blood 100, 3861–3868 (2002).

    Article  CAS  Google Scholar 

  28. Aoki, M., Pawankar, R., Niimi, Y. & Kawana, S. Mast cells in basal cell carcinoma express VEGF, IL-8 and RANTES. Int. Arch. Allergy Immunol. 130, 216–223 (2003).

    Article  CAS  Google Scholar 

  29. Kimura, Y., Pawankar, R., Aoki, M., Niimi, Y. & Kawana, S. Mast cells and T cells in Kimura's disease express increased levels of interleukin-4, interleukin-5, eotaxin and RANTES. Clin. Exp. Allergy 32, 1787–1793 (2002).

    Article  CAS  Google Scholar 

  30. Leppert, D. et al. Stimulation of matrix metalloproteinase-dependent migration of T cells by eicosanoids. Faseb J. 9, 1473–1481 (1995).

    Article  CAS  Google Scholar 

  31. Morita, H., Takeda, K., Yagita, H. & Okumura, K. Immunosuppressive effect of leukotriene B4 receptor antagonist in vitro. Biochem. Biophys. Res. Commun. 264, 321–326 (1999).

    Article  CAS  Google Scholar 

  32. Gualde, N., Atluru, D. & Goodwin, J.S. Effect of lipoxygenase metabolites of arachidonic acid on proliferation of human T cells and T cell subsets. J. Immunol. 134, 1125–1129 (1985).

    CAS  PubMed  Google Scholar 

  33. Payan, D.G., Missirian-Bastian, A. & Goetzl, E.J. Human T-lymphocyte subset specificity of the regulatory effects of leukotriene B4. Proc. Natl. Acad. Sci. USA 81, 3501–3505 (1984).

    Article  CAS  Google Scholar 

  34. Bailie, M.B. et al. Leukotriene-deficient mice manifest enhanced lethality from Klebsiella pneumonia in association with decreased alveolar macrophage phagocytic and bactericidal activities. J. Immunol. 157, 5221–5224 (1996).

    CAS  PubMed  Google Scholar 

  35. Griffiths, R.J. et al. Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice. J. Exp. Med. 185, 1123–1129 (1997).

    Article  CAS  Google Scholar 

  36. Turner, C.R. et al. In vitro and in vivo effects of leukotriene B4 antagonism in a primate model of asthma. J. Clin. Invest. 97, 381–387 (1996).

    Article  CAS  Google Scholar 

  37. Henderson, W.R., Jr. et al. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J. Exp. Med. 184, 1483–1494 (1996).

    Article  CAS  Google Scholar 

  38. Malaviya, R. & Abraham, S.N. Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis. J. Leukoc. Biol. 67, 841–846 (2000).

    Article  CAS  Google Scholar 

  39. Ramos, B.F., Zhang, Y., Qureshi, R. & Jakschik, B.A. Mast cells are critical for the production of leukotrienes responsible for neutrophil recruitment in immune complex-induced peritonitis in mice. J. Immunol. 147, 1636–1641 (1991).

    CAS  PubMed  Google Scholar 

  40. Iwamoto, I., Tomoe, S., Tomioka, H. & Yoshida, S. Leukotriene B4 mediates substance P-induced granulocyte infiltration into mouse skin. Comparison with antigen-induced granulocyte infiltration. J. Immunol. 151, 2116–2123 (1993).

    CAS  PubMed  Google Scholar 

  41. Lefrancois, L. & Masopust, D. T cell immunity in lymphoid and non-lymphoid tissues. Curr. Opin. Immunol. 14, 503–508 (2002).

    Article  CAS  Google Scholar 

  42. Swanson, B.J., Murakami, M., Mitchell, T.C., Kappler, J. & Marrack, P. RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process. Immunity 17, 605–615 (2002).

    Article  CAS  Google Scholar 

  43. Oshiba, A. et al. Passive transfer of immediate hypersensitivity and airway hyperresponsiveness by allergen-specific immunoglobulin (Ig) E and IgG1 in mice. J. Clin. Invest. 97, 1398–1408 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank R.C. Murphy for contributions to this work, and B. Townend, S. Sobus and J. Loomis for technical assistance with cell sorting. This work was supported by US Public Health Service grants AI-17134, AI-18785, AI-52225 and AI-22295 (to P.M. and J.K.), and AI-39773 (to J.C.C.). V.L.O. is supported by a National Research Service Award from the National Institutes of Health. B.J.S. is supported by a Norman B. Levy Fellowship in Basic Immunological Research from National Jewish Medical and Research Center.

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Correspondence to Vanessa L Ott.

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Ott, V., Cambier, J., Kappler, J. et al. Mast cell–dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat Immunol 4, 974–981 (2003). https://doi.org/10.1038/ni971

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