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


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.

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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.

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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.

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Correspondence to Rosemarie H. DeKruyff.

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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).

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