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:

Differential requirement for CD18 in T-helper effector homing

Abstract

To understand the integrin requirements of T-helper (TH) effector subsets, we investigated the contribution of CD18 (β2 integrin) to TH1 and TH2 function in vitro and in relevant disease models. CD18-deficient (Itgb2−/−) T cells showed largely normal in vitro function. Compared with wild-type mice, Itgb2−/− mice were better able to resolve Leishmania major infection and generated a superior TH1 immune response, as assessed from draining lymph nodes. In contrast, TH2-dependent allergic lung disease was markedly impaired in mutant mice. In both models, development of TH1 and TH2 cells in spleens was normal, but accumulation of TH2 (not TH1) cells at inflammatory sites was reduced. Thus, CD18 is selectively required for TH2, but not TH1, homing and has a minimal influence on T-effector development. These findings suggest a new integrin-based therapeutic approach in which the outcomes of diverse diseases may be favorably influenced by altering the homing of TH2 cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: T-cell function in the absence of CD18.
Figure 2: CD18-null mice are highly resistant to L. major infection.
Figure 3: CD18 deficiency causes dissociation of allergic lung inflammation from antibody production.
Figure 4: A TH defect precludes allergic lung responses in Itgb2−/− mice.
Figure 5: CD18 deficiency precludes TH2 homing.
Figure 6: CD18 blockade abrogates allergic lung disease.

Similar content being viewed by others

References

  1. Mosmann, T.R. & Coffman, R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    Article  CAS  Google Scholar 

  2. Abbas, A.K., Murphy, K.M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    Article  CAS  Google Scholar 

  3. Szabo, S.J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  Google Scholar 

  4. Ouyang, W. et al. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12, 27–37 (2000).

    Article  CAS  Google Scholar 

  5. Kaplan, M.H., Schindler, U., Smiley, S.T. & Grusby, M.J. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4, 313–319 (1996).

    Article  CAS  Google Scholar 

  6. Fowell, D.J. et al. Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Immunity 11, 399–409 (1999).

    Article  CAS  Google Scholar 

  7. Syrbe, U., Siveke, J. & Hamann, A. Th1/Th2 subsets: distinct differences in homing and chemokine receptor expression? Springer Semin. Immunopathol. 21, 263–285 (1999).

    Article  CAS  Google Scholar 

  8. Austrup, F. et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature 385, 81–83 (1997).

    Article  CAS  Google Scholar 

  9. Berlin, C. et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74, 185–185 (1993).

    Article  CAS  Google Scholar 

  10. Paller, A.S., Nanda, V., Spates, C. & O'Gorman, M. Leukocyte adhesion deficiency: recurrent childhood skin infections. J. Am. Acad. Dermatol. 31, 316–319 (1994).

    Article  CAS  Google Scholar 

  11. Scharffetter-Kochanek, K. et al. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J. Exp. Med. 188, 119–131 (1998).

    Article  CAS  Google Scholar 

  12. Brockdorff, J. et al. Interleukin-2 induces beta2-integrin-dependent signal transduction involving the focal adhesion kinase-related protein B (fakB). Proc. Natl. Acad. Sci. USA 95, 6959–6964 (1998).

    Article  CAS  Google Scholar 

  13. Heinzel, F.P., Sadick, M.D., Holaday, B.J., Coffman, R.L. & Locksley, R.M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J. Exp. Med. 169, 59–72 (1989).

    Article  CAS  Google Scholar 

  14. Corry, D.B. et al. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 183, 109–117 (1996).

    Article  CAS  Google Scholar 

  15. Jones, D.A., McIntire, L.V., Smith, C.W. & Picker, L.J. A two-step adhesion cascade for T cell/endothelial cell interactions under flow conditions. J. Clin. Invest. 94, 2443–2450 (1994).

    Article  CAS  Google Scholar 

  16. Abitorabi, M.A. et al. Differential expression of homing molecules on recirculating lymphocytes from sheep gut, peripheral, and lung lymph. J. Immunol. 156, 3111–3117 (1996).

    CAS  PubMed  Google Scholar 

  17. McDermott, M.R. & Bienenstock, J. Evidence for a common mucosal immunologic system I. Migration of B immunoblasts into intestinal, respiratory, and genital tissues. J. Immunol. 122, 1892–1898 (1979).

    CAS  PubMed  Google Scholar 

  18. Schnare, M. et al. Toll-like receptors control activation of adaptive immune responses. Nat. Immunol. 2, 947–950 (2001).

    Article  CAS  Google Scholar 

  19. Walsh, G.M. et al. IL-5 enhances the in vitro adhesion of human eosinophils, but not neutrophils, in a leucocyte integrin (CD11/18)-dependent manner. Immunology 71, 258–265 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kaneko, M., Horie, S., Kato, M., Gleich, G.J. & Kita, H. A crucial role for beta 2 integrin in the activation of eosinophils stimulated by IgG. J. Immunol. 155, 2631–2641 (1995).

    CAS  PubMed  Google Scholar 

  21. Sanders, V.M., Snyder, J.M., Uhr, J.W. & Vitetta, E.S. Characterization of the physical interaction between antigen-specific B and T cells. J. Immunol. 137, 2395–2404 (1986).

    CAS  PubMed  Google Scholar 

  22. Fischer, H. et al. Stimulation of human naive and memory T helper cells with bacterial superantigen. Naive CD4+45RA+ T cells require a costimulatory signal mediated through the LFA-1/ICAM-1 pathway. J. Immunol. 148, 1993–1998 (1992).

    CAS  PubMed  Google Scholar 

  23. Green, J.M., Zheng, X.G., Shimizu, Y., Thompson, C.B. & Turka, L.A. T cell receptor stimulation, but not CD28 costimulation, is dependent on LFA-1-mediated events. Eur. J. Immunol. 24, 265–272 (1994).

    Article  CAS  Google Scholar 

  24. Schonlau, F. et al. In experimental leishmaniasis deficiency of CD18 results in parasite dissemination associated with altered macrophage functions and incomplete Th1 cell response. Eur. J. Immunol. 30, 2729–2740 (2000).

    Article  CAS  Google Scholar 

  25. Xu, B. et al. Lymphocyte homing to bronchus-asssociated lymphoid tissue (BALT) is mediated by L-selectin/PNAD, α4β1 integrin/VCAM-1, and LFA-1 adhesion pathways. J. Exp. Med. 197, 1255–1267 (2003).

    Article  CAS  Google Scholar 

  26. Shimaoka, M. et al. Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell. 112, 99–111 (2003).

    Article  CAS  Google Scholar 

  27. Sasaki, K. et al. Differential regulation of VLA-2 expression on T(h)1 and T(h)2 cells: a novel marker for the classification of T(h) subsets. Inter. Immunol. 15, 701–710 (2003).

    Article  CAS  Google Scholar 

  28. Schuh, J.M. et al. Airway hyperresponsiveness, but not airway remodeling, is attenuated during chronic pulmonary allergic responses to Aspergillus in CCR4−/− mice. FASEB J. Online 16, 1313–1315 (2002).

    Article  CAS  Google Scholar 

  29. Kawasaki, S. et al. Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hyperresponsiveness in mice. J. Immunol. 166, 2055–2062 (2001).

    Article  CAS  Google Scholar 

  30. Wegner, C.D. et al. Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma. Science 247, 456–459 (1990).

    Article  CAS  Google Scholar 

  31. Medoff, B.D. et al. IFN-gamma-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma. J. Immunol. 168, 5278–5286 (2002).

    Article  CAS  Google Scholar 

  32. Corry, D.B. et al. Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice. Mol. Med. 4, 344–355 (1998).

    Article  CAS  Google Scholar 

  33. Grunig, G. et al. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J. Exp. Med. 185, 1089–1099 (1997).

    Article  CAS  Google Scholar 

  34. Corry, D.B., Reiner, S.L., Linsley, P.S. & Locksley, R.M. Differential effects of blockade of CD28-B7 in the development of Th1 or Th2 effector cells in experimental leishmaniasis. J. Immunol. 153, 4142–4148 (1994).

    CAS  PubMed  Google Scholar 

  35. Soong, L. et al. Disruption of CD40-CD40 ligand interactions results in an enhanced susceptibility to Leishmania amazonensis infection. Immunity 4, 263–273 (1996).

    Article  CAS  Google Scholar 

  36. Wang, Z.E., Reiner, S.L., Zheng, S., Dalton, D.K. & Locksley, R.M. CD4+ effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major. J. Exp. Med. 179, 1367–1371 (1994).

    Article  CAS  Google Scholar 

  37. Corry, D.B. et al. Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency. Nat. Immunol. 3, 347–353 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants HL69585-01 (to D.B.C.), HL64061-01 (to F.K.) and F32-HL09657-02 (to H.L.) from the National Institutes of Health. We thank J. Xu and Y. Qian for technical assistance, and J.R. Rodgers, B.W. McIntyre and C.M. Ballantyne for helpful discussions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David B Corry.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, SH., Prince, J., Rais, M. et al. Differential requirement for CD18 in T-helper effector homing. Nat Med 9, 1281–1286 (2003). https://doi.org/10.1038/nm932

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm932

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