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:

Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family

Nature Immunology volume 2, pages 1109–1116 (2001)Cite this article

Abstract

To simplify the analysis of asthma susceptibility genes located at human chromosome 5q23-35, we examined congenic mice that differed at the homologous chromosomal segment. We identified a Mendelian trait encoded by T cell and Airway Phenotype Regulator (Tapr). Tapr is genetically distinct from known cytokine genes and controls the development of airway hyperreactivity and T cell production of interleukin 4 (IL-4) and IL-13. Positional cloning identified a gene family that encodes T cell membrane proteins (TIMs); major sequence variants of this gene family (Tim) completely cosegregated with Tapr. The human homolog of TIM-1 is the hepatitis A virus (HAV) receptor, which may explain the inverse relationship between HAV infection and the development of atopy.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: HBA cytokine and AHR responses resemble DBA/2 phenotypes.
Figure 2: Regions of HBA chromosome 11 were inherited from DBA/2.
Figure 3: Tapr cosegregates with Kim1sscp
Figure 4: Mouse chromosome 11 interval containing Tapr is highly homologous to human 5q33.
Figure 5: Identification of the Tim gene family and major polymorphisms in TIM-1 and TIM-3.
Figure 6: Tapr regulates CD4+ T cell IL-4 and IL-13 responses.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Hjern, A., Haglund, B. & Hedlin, G. Ethnicity, childhood environment and atopic disorder. Clin. Exp. Allergy 30, 521–528 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Palmer, L. J. & Cookson, W. O. Genomic approaches to understanding asthma. Genome Res. 10, 1280–1287 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. McNally, N. J., Phillips, D. R. & Williams, H. C. The problem of atopic eczema: aetiological clues from the environment and lifestyles. Soc. Sci. Med. 46, 729–741 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Woolcock, A. J. & Peat, J. K. Evidence for the increase in asthma worldwide. Ciba Found. Symp. 206, 122–134 (1997).

    CAS  PubMed  Google Scholar 

  5. Asher, M. I. et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur. Respir. J. 8, 483–491 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Weiss, K. B. & Sullivan, S. D. The health economics of asthma and rhinitis. I. Assessing the economic impact. J. Allergy Clin. Immunol. 107, 3–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Shirakawa, T., Enomoto, T., Shimazu, S. & Hopkin, J. M. The inverse association between tuberculin responses and atopic disorder. Science 275, 77–79 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Matricardi, P. M. et al. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. Brit. J. Med. 314, 999–1003 (1997).

    Article  CAS  Google Scholar 

  9. Marsh, D. G. et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 264, 1152–1156 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Postma, D. S. et al. Genetic susceptibility to asthma—bronchial hyperresponsiveness coinherited with a major gene for atopy. N. Engl. J. Med. 333, 894–900 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. The Collaborative Study on the Genetics of Asthma (CSGA). Nature Genet. 15, 389–392 (1997).

  12. Hershey, G. K., Friedrich, M. F., Esswein, L. A., Thomas, M. L. & Chatila, T. A. The association of atopy with a gain-of-function mutation in the α subunit of the interleukin-4 receptor. N. Engl. J. Med. 337, 1720–1725 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Ober, C. et al. Variation in the interleukin 4-receptor α gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am. J. Hum. Genet. 66, 517–526 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cookson, W. O. & Hopkin, J. M. Dominant inheritance of atopic immunoglobulin-E responsiveness. Lancet 1, 86–88 (1988).

    Article  CAS  PubMed  Google Scholar 

  15. Cookson, W. O., Sharp, P. A., Faux, J. A. & Hopkin, J. M. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 1, 1292–1295 (1989).

    Article  CAS  PubMed  Google Scholar 

  16. Howard, T. D., Meyers, D. A. & Bleecker, E. R. Mapping susceptibility genes for asthma and allergy. J. Allergy Clin. Immunol. 105, 477–481 (2000).

    Article  Google Scholar 

  17. Yokouchi, Y. et al. Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families. Genomics 66, 152–160 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Noguchi, E. et al. Evidence for linkage between asthma/atopy in childhood and chromosome 5q31-q33 in a Japanese population. Am. J. Respir. Crit. Care Med. 156, 1390–1393 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Loots, G. G. et al. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288, 136–140 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Walley, A. J., Wiltshire, S., Ellis, C. M. & Cookson, W. O. Linkage and allelic association of chromosome 5 cytokine cluster genetic markers with atopy and asthma associated traits. Genomics 72, 15–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Juniper, E. F., Frith, P. A., Dunnett, C., Cockcroft, D. W. & Hargreave, F. E. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 33, 705–710 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hargreave, F. E. et al. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J. Allergy Clin. Immunol. 68, 347–355 (1981).

    Article  CAS  PubMed  Google Scholar 

  23. Potter, M. et al. A BALB/c congenic strain of mice that carries a genetic locus (Ityr) controlling resistance to intracellular parasites. Infect. Immun. 40, 1234–1235 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ruscetti, S., Matthai, R. & Potter, M. Susceptibility of BALB/c mice carrying various DBA/2 genes to development of Friend murine leukemia virus-induced erythroleukemia. J. Exp. Med. 162, 1579–1587 (1985).

    Article  CAS  PubMed  Google Scholar 

  25. Potter, M., Mushinski, E. B., Wax, J. S., Hartley, J. & Mock, B. A. Identification of two genes on chromosome 4 that determine resistance to plasmacytoma induction in mice. Cancer Res. 54, 969–975 (1994).

    CAS  PubMed  Google Scholar 

  26. DeKruyff, R. H., Fang, Y. & Umetsu, D. T. IL-4 synthesis by in vivo primed keyhole limpet hemocyanin-specific CD4+ T cells. I. Influence of antigen concentration and antigen- presenting cell type. J. Immunol. 149, 3468–3476 (1992).

    CAS  PubMed  Google Scholar 

  27. Hansen, G., Berry, G., DeKruyff, R. H. & Umetsu, D. T. Allergen-specific TH1 cells fail to counterbalance TH2 cell-induced airway hyperreactivity but cause severe airway inflammation. J. Clin. Invest. 103, 175–183 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Cohn, L., Homer, R. J., Marinov, A., Rankin, J. & Bottomly, K. Induction of airway mucus production By T helper 2 (TH2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production. J. Exp. Med. 186, 1737–1747 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. The Jackson Laboratory Mouse Genome Informatics (The Jackson Laboratory, Bar Harbor, ME, 2001).

  31. Silver, L. M. Mouse Genetics: Concepts and applications (Oxford University Press, New York, 1995).

    Google Scholar 

  32. Brady, K. P. et al. Genetic mapping of 262 loci derived from expressed sequences in a murine interspecific cross using single-strand conformational polymorphism analysis. Genome. Res. 7, 1085–1093 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ichimura, T. et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J. Biol. Chem. 273, 4135–4142 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Teuscher, C. et al. Sequence polymorphisms in the chemokines Scya1 (TCA-3), Scya2 (monocyte chemoattractant protein (MCP)-1), and Scya12 (MCP-5) are candidates for eae7, a locus controlling susceptibility to monophasic remitting/nonrelapsing experimental allergic encephalomyelitis. J. Immunol. 163, 2262–2266 (1999).

    CAS  PubMed  Google Scholar 

  35. Guler, M. L. et al. Tpm1, a locus controlling IL-12 responsiveness, acts by a cell- autonomous mechanism. J. Immunol. 162, 1339–1347 (1999).

    CAS  PubMed  Google Scholar 

  36. Van Etten, W. J. et al. Radiation hybrid map of the mouse genome. Nature Genet. 22, 384–387 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. McPherson, J. D. et al. A physical map of the human genome. Nature 409, 934–941 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. 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  PubMed  Google Scholar 

  41. Ryu, S., Zhou, S., Ladurner, A. G. & Tjian, R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446–450 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Monney, L. et al. Identification and characterization of novel cell surface molecules expressed on TH1 cells. Scand. J. Immunol. 54, 35 (2001).

    Google Scholar 

  43. Feigelstock, D., Thompson, P., Mattoo, P., Zhang, Y. & Kaplan, G. G. The human homolog of HAVcr-1 codes for a hepatitis A virus cellular receptor. J. Virol. 72, 6621–6628 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Feigelstock, D., Thompson, P., Mattoo, P. & Kaplan, G. G. Polymorphisms of the hepatitis A virus cellular receptor 1 in African green monkey kidney cells result in antigenic variants that do not react with protective monoclonal antibody 190/4. J. Virol. 72, 6218–6222 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hsieh, C. S., Heimberger, A. B., Gold, J. S., O'Garra, A. & Murphy, K. M. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an αβ T-cell-receptor transgenic system. Proc. Natl Acad. Sci. USA 89, 6065–6069 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kamogawa, Y., Minasi, L. A., Carding, S. R., Bottomly, K. & Flavell, R. A. The relationship of IL-4- and IFNγ-producing T cells studied by lineage ablation of IL-4-producing cells. Cell 75, 985–995 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Matricardi, P. M., Rosmini, F., Rapicetta, M., Gasbarrini, G. & Stroffolini, T. Atopy, hygiene, and anthroposophic lifestyle. San Marino Study Group. Lancet 354, 430 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Matricardi, P. M. et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. Brit. J. Med. 320, 412–417 (2000).

    Article  CAS  Google Scholar 

  49. Wu, C. et al. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nature Immunol. 2, 410–414 (2001).

    Article  CAS  Google Scholar 

  50. Tatsuo, H., Ono, N., Tanaka, K. & Yanagi, Y. SLAM (CDw150) is a cellular receptor for measles virus. Nature 406, 893–897 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Schneider-Schaulies, J. Cellular receptors for viruses: links to tropism and pathogenesis. J. Gen. Virol. 81, 1413–1429 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Trowsdale, J. Genetic and Functional Relationships between MHC and NK Receptor Genes. Immunity 15, 363–374 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Murphy, K. M., Heimberger, A. B. & Loh, D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250, 1720–1723 (1990).

    Article  CAS  PubMed  Google Scholar 

  55. Hansen, G., Yeung, V. P., Berry, G., Umetsu, D. T. & DeKruyff, R. H. Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: role of CD8+ T cells and IL-18. J. Immunol. 164, 223–230 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Hamelmann, E. et al. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156, 766–775 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Lahn, M. et al. Negative regulation of airway responsiveness that is dependent on γδ T cells and independent of αβ T cells. Nature Med. 5, 1150–1156 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Yeung, V. P., Gieni, R. S., Umetsu, D. T. & DeKruyff, R. H. Heat-killed Listeria monocytogenes as an adjuvant converts established murine TH2-dominated immune responses into TH1-dominated responses. J. Immunol. 161, 4146–4152 (1998).

    CAS  PubMed  Google Scholar 

  59. Inaba, K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702 (1992).

    Article  CAS  PubMed  Google Scholar 

  60. Macaulay, A. E., DeKruyff, R. H., Goodnow, C. C. & Umetsu, D. T. Antigen-specific B cells preferentially induce CD4+ T cells to produce IL–4. J. Immunol. 158, 4171–4179 (1997).

    CAS  PubMed  Google Scholar 

  61. Macaulay, A. E., DeKruyff, R. H. & Umetsu, D. T. Antigen-primed T cells from B cell-deficient JHD mice fail to provide B cell help. J. Immunol. 160, 1694–1700 (1998).

    CAS  PubMed  Google Scholar 

  62. Turkey, J. W. Exploratory Data Analysis (Addison-Wesley, NY, 1977).

    Google Scholar 

  63. Frazer, K. A. et al. Computational and biological analysis of 680 kb of DNA sequence from the human 5q31 cytokine gene cluster region. Genome Res. 7, 495–512 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Zhu, Y. et al. Genomic interval engineering of mice identifies a novel modulator of triglyceride production. Proc. Natl Acad. Sci. USA 97, 1137–1142 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank G. Hansen for help with preliminary airway hyperreactivity studies; V. Pete Yeung for help with mouse studies; D. Beier for input regarding Kim1; T. Gunn for helpful discussions; and D. Schlesinger, J. Schwartz, D. Cox, K. Frazer, M. Olivier and A. Sidow for help with map refinement and analysis. Supported by NIH-AI-24571, the Stanford University School of Medicine Medical Scholars Program, PHS grant numbers CA09302 (to J. J. M.) and CA84500 (to G. J. F.) from the National Cancer Institute and Mr. and Mrs. C. Aronstam.

Author information

Authors and Affiliations

  1. Division of Immunology and Allergy, Department of Pediatrics and the Howard Hughes Institute, Stanford University, Stanford, 94305-5208, CA, USA

    Jennifer J. McIntire, Sarah E. Umetsu, Omid Akbari, Dale T. Umetsu & Rosemarie H. DeKruyff

  2. National Cancer Institute, Bethesda, 20892-4255, MD, USA

    Michael Potter

  3. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA

    Vijay K. Kuchroo

  4. Departments of Pediatrics and Genetics and the Howard Hughes Institute, Stanford University, Stanford, 94305-5208, CA, USA

    Gregory S. Barsh

  5. Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard University, Boston, 02115, MA, USA

    Gordon J. Freeman

Authors
  1. Jennifer J. McIntire
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah E. Umetsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Omid Akbari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Potter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vijay K. Kuchroo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregory S. Barsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gordon J. Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dale T. Umetsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rosemarie H. DeKruyff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosemarie H. DeKruyff.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McIntire, J., Umetsu, S., Akbari, O. et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2, 1109–1116 (2001). https://doi.org/10.1038/ni739

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni739

This article is cited by

Search

Advanced 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