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Expression of Aire and the Early Wave of Apoptosis in Spermatogenesis¹

Claudia E. Schaller^*, Clifford L. Wang^*, Gabriele Beck-Engeser^*, Lindsie Goss^*, Hamish S. Scott, Mark S. Anderson and Matthias Wabl^2,*

^* Department of Microbiology and Immunology, Diabetes Center, University of California, San Francisco, CA 94143; and Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia

Expression of the autoimmune regulator (Aire) protein in mice and humans is thought to be restricted to the medullary epithelial and monocyte-dendritic cells of the thymus. There it mediates expression and presentation of a large variety of proteins, including those that are peripheral organ-specific and are not expressed by other thymocytes. In this way, self-reactive T lymphocytes that would attack peripheral cells producing these proteins are confronted with the self-Ags and, as a consequence, are deleted. In this study, we show that Aire mRNA is also expressed in the testis—another tissue with promiscuous gene expression. Aire protein, however, is expressed only sporadically in spermatogonia and spermatocytes. Transcription of genes that are under Aire control in the thymus is unaffected by Aire in the testis. However, in mice with a disrupted Aire gene, the scheduled apoptotic wave of germ cells, which is necessary for normal mature spermatogenesis, is reduced, and sporadic apoptosis in adults is increased. Because Rag-1 deficiency does not abolish the effect, the adaptive immune system is not involved. We suggest that there is a link between the scheduled and sporadic apoptotic processes and propose that scheduled apoptosis provides a counterselection mechanism that keeps the germline stable.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Grants R01 AI041570 and a BioSTAR grant funded by the University of California and Medarex (to M.W.).

² Address correspondence and reprint requests to Dr. Matthias Wabl, Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143. E-mail address: mutator{at}ucsf.edu

³ Abbreviations used in this paper: Aire, autoimmune regulator; APECED, polyendocrinopathy-candidiasis-ectodermal dystrophy.