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The Magnitude of Thymic Output Is Genetically Determined through Controlled Intrathymic Precursor T Cell Proliferation¹

Gaël Dulude^2,*,||, Remi Cheynier^2,#, Dominique Gauchat^*,||, Ali Abdallah^*,||, Nadia Kettaf^*,||, Rafick-Pierre Sékaly^2,3,*,,,,|| and Sophie Gratton^2,*,¶,||

^* Laboratoire d’Immunologie, Centre de Recherches du Centre Hospitalier de l’Université Montréal, Saint-Luc, Montréal, Québec, Canada; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada; Département de Microbiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; ^¶ Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; ^|| Institut National de la Santé et de la Recherche Médicale, Unité 743, Centre de Recherches du Centre Hospitalier de l’Université Montréal, Université de Montréal, Montréal, Québec, Canada; and ^# Département de Virologie, Institut Pasteur, Paris, France

The thymus plays a crucial role in providing the immune system with naive T cells showing a diverse TCR repertoire. Whereas the diversity of thymic production is mainly ensured by TCR rearrangement at both the TRA and TRB loci, the number of cells reaching the double-positive differentiation stage defines the extent of thymic output. A quantitative analysis of TCR excision circles (TREC; signal-joint TRECs and DJβTRECs) produced at different stages of thymopoiesis was performed in nine laboratory mouse strains. The results clearly demonstrate that the magnitude of thymic output is directly proportional to the extent of proliferation in the double-negative 4 thymocyte subset. Strikingly, intrathymic precursor T cell proliferation was found to be strain dependent, thus suggesting a genetic regulation of thymic output. The inherited character of thymic output was further confirmed by the transmission of the phenotype in a recessive fashion in F₁ progeny of the different parental strains. Our results provide the first demonstration of the genetic regulation of thymic output.

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 This work was supported by grants to R.-P.S. from the Canadian Institute of Health Research and the Canadian Network for Vaccine and Immunotherapeutics. R.-P.S. is the Canada Research Chair in Human Immunology.

² G.D., R.C., R.-P.S., and S.G. contributed equally.

³ Address correspondence and reprint requests to Dr. Rafick-Pierre Sékaly, Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Saint-Luc, 264 René Lévesque Est, Montréal, Québec H2X1P1, Canada. E-mail address: rafick-pierre.sekaly{at}umontreal.ca

⁴ Abbreviations used in this paper: TREC, TCR excision circle; sj, signal joint; LN, lymph node; DP, double positive; DN, double negative; SP, single positive; ISP, intermediate simple positive; RTE, recent thymic emmigrant; sj/βTREC ratio, the ratio of sjTREC to DJβTREC frequencies; CD62L, L-selectin.