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Evolutionarily conserved and divergent regions of the Autoimmune Regulator (Aire) gene: a comparative analysis

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Abstract

During T cell differentiation, medullary thymic epithelial cells (MTEC) expose developing T cells to tissue-specific antigens. MTEC expression of such self-antigens requires the transcription factor autoimmune regulator (Aire). In mammals, defects in aire result in multi-tissue, T cell-mediated autoimmunity. Because the T cell receptor repertoire is randomly generated and extremely diverse in all jawed vertebrates, it is likely that an aire-dependent T cell tolerance mechanism also exists in nonmammalian vertebrates. We have isolated aire genes from animals in all gnathostome classes except the cartilaginous fish by a combination of molecular techniques and scanning of expressed sequence tags and genomic databases. The deduced amino acid sequences of Aire were compared among mouse, human, opossum, chicken, Xenopus, zebrafish, and pufferfish. The first of two plant homeodomains (PHD) in human Aire and regions associated with nuclear and cytoplasmic localization are evolutionarily conserved, while other domains are either absent or divergent in one or more vertebrate classes. Furthermore, the second zinc-binding domain previously named Aire PHD2 appears to have greater sequence similarity with Ring finger domains than to PHD domains. Point mutations in defective human aire genes are generally found in the most evolutionarily conserved regions of the protein. These findings reveal a very rapid evolution of certain regions of aire during vertebrate evolution and support the existence of an aire-dependent mechanism of T cell tolerance dating back at least to the emergence of bony fish.

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Acknowledgments

This work has been funded by the NIH (R01AI27877).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Maryland, Baltimore, 660 West Redwood Street, HH324, Baltimore, MD, 21201, USA

    Mark Saltis, Michael F. Criscitiello, Yuko Ohta & Martin F. Flajnik

  2. Division of Pediatrics, The Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA

    Nikolaus S. Trede

  3. Division of Molecular Biology, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA

    Matthew Keefe

  4. Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba, 278-0022, Japan

    Ryo Goitsuka

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  1. Mark Saltis
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  2. Michael F. Criscitiello
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  3. Yuko Ohta
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  4. Matthew Keefe
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  5. Nikolaus S. Trede
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  6. Ryo Goitsuka
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  7. Martin F. Flajnik
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Corresponding author

Correspondence to Martin F. Flajnik.

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Supplemental Fig. 1

cDNA sequence of X. tropicalis (X.t.) aire. The overhead line denotes overlap of one or more EST sequences. Primers underlined. Bold letters denote the probe region used in Northern blotting and cDNA library screening. Amino acid sequence of a partial X. laevis (X.l.) sequence aligned to the X. tropicalis sequence (PDF 132 kb)

Supplemental Fig. 2

Chicken genomic fragment amplified by PCR. The bold sequence corresponds to exons derived from PCR amplification of cDNA. Primers used for PCR amplification are underlined. Major splice junctions are denoted by black triangles. Minor splice junctions are denoted by gray triangles. A turkey genomic fragment is aligned for a portion of the chicken sequence. The sequence in the gray box is consistent with an identified microsatellite identified in the turkey suggesting an area of genomic instability (PDF 139 kb)

Supplemental Fig. 3

Zebrafish alignment to other teleost fishes. Aire from two species of pufferfish were reconstructed based on alignment to zebrafish Aire. Sequences were subsequently aligned using Clustal W followed by manual adjustment (PDF 116 kb)

Supplemental Fig. 4

Pairwise sequence identity comparison of the putative Aire amino acid sequences aligned by exon. For reference, the equivalent human domain is listed above each alignment. Bioedit (Hall 1999) was used to create sequence identity matrices (PDF 242 kb)

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Saltis, M., Criscitiello, M.F., Ohta, Y. et al. Evolutionarily conserved and divergent regions of the Autoimmune Regulator (Aire) gene: a comparative analysis. Immunogenetics 60, 105–114 (2008). https://doi.org/10.1007/s00251-007-0268-9

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  • DOI: https://doi.org/10.1007/s00251-007-0268-9

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