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Autoimmunity during Thymectomy-Induced Lymphopenia: Role of Thymus Ablation and Initial Effector T Cell Activation Timing in Nonobese Diabetic Mice¹

Marie-Claude Gagnerault,^* Olivia Lanvin, Virginie Pasquier, Corinne Garcia, Diane Damotte, Bruno Lucas,^¶|| and Françoise Lepault^2¶||

^*INSERM Unité 561, René Descartes University, Saint-Vincent-de-Paul Hospital, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8603, René Descartes University, Necker Hospital, Paris, France; Medicine School, René Descartes University, Paris, France; Pathologic Anatomy Department, Georges Pompidou European Hospital, Paris, France; ^¶Cochin Institute, René Descartes University, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Cochin Hospital, Paris, France; and ^||INSERM Unité 567, Cochin Hospital, Paris, France

Autoimmune diseases develop in selected normal mouse strains when thymectomy (Tx) is performed at 3 days of age (d3-Tx). Insufficient T cell regulation after Tx may result from a defect in regulatory T (Treg) cells or from an augmented effector T (Teff) cell number/pathogenicity. We have previously shown that Tx at 3 wk (wk3-Tx), the age of massive islet Ag release, accelerates diabetes onset. We now have determined diabetes incidence in d3-Tx nonobese diabetic mice and compared the frequency and function of their Teff and Treg cells with those of wk3-Tx mice. We found that d3-Tx had no effect on diabetes incidence, but induced gastritis. After day 3 and week 3 Tx, Treg cells were fully competent and their frequency increased. The number of diabetogenic T cells was greatly amplified after wk3-Tx and likely overcame Treg cell control, leading to an early tolerance breakdown. By contrast, in d3-Tx mice, activation concerned few cells and Teff cell amplification remained controlled. This suggests that Tx enhances autoimmunity when it coincides with the first encounter of autoreactive T cells with their cognate Ag. The relationship between Tx-induced lymphopenia, tissue remodeling, and autoimmunity is discussed.

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 recurrent funding from INSERM and Centre National de la Recherche Scientifique.

² Address correspondence and reprint requests to Dr. Françoise Lepault, Institut Cochin, INSERM Unité 567, Département Immunologie Hématologie, 27 rue du faubourg Saint Jacques, 75014 Paris, France. E-mail address: francoise.lepault{at}inserm.fr

³ Abbreviations used in this paper: Tx, thymectomy; NOD, nonobese diabetic; Treg, regulatory T; Teff, effector T; PLN, pancreatic LN; perLN, peripheral LN; MLN, mesenteric LN; d3-Tx, thymectomy at 3 days; wk3-Tx, thymectomy at 3 wk; LIP, lymphopenia-induced proliferation; LN, lymph node; GITR, glucocorticoid-induced TNFR-related protein 1.