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Pathogenic Effector T Cell Enrichment Overcomes Regulatory T Cell Control and Generates Autoimmune Gastritis¹

João P. Monteiro^2,*,,, Julia Farache^2,*,, Ana Carolina Mercadante^*, Julio A. Mignaco^¶, Martin Bonamino^* and Adriana Bonomo^3,*,

^* Divisão de Medicina Experimental, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil; Programa de Pós-graduação em Biofísica, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil; Programa MD/PhD de formação em pesquisa médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil; Departamento de Imunologia, Instituto de Microbiologia Prof. Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil; and ^¶ Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Brazil

Regulatory T cells (Treg) deficiency leads to a severe, systemic, and lethal disease, as showed in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome patients, and scurfy mouse. Postneonatal thymectomy autoimmune gastritis has also been attributed to the absence of Tregs. In this case however, disease is mild, organ-specific, and, more important, it is not an obligatory outcome. We addressed this paradox comparing T cell compartments in gastritis-susceptible and resistant animals. We found that neonatal thymectomy-induced gastritis is not caused by the absence of Tregs. Instead of this, it is the presence of gastritogenic T cell clones that determines susceptibility to disease. The expansion of such clones under lymphopenic conditions results in a reduced Treg:effector T cell ratio that is not enough to control gastritis development. Finally, the presence of gastritogenic clones is determined by the amount of gastric Ag expressed in the neonatal thymus, emphasizing the importance of effector repertoire variability, present even in genetically identical subjects, to organ-specific autoimmune disease susceptibility.

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 Conselho Nacional Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Rio de Janeiro, and Swiss Bridge Foundations Grants.

² João P. Monteiro and Julia Farache contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Adriana Bonomo, Rua André Cavalcanti 37/6° andar, Centro, CEP 20231-050, Rio de Janeiro, Brazil. E-mail address: abonomo{at}inca.gov.br

⁴ Abbreviations used in this paper: Treg, regulatory T cell; Teff, effector T cell; AIG, autoimmune gastritis; GLN, gastric lymph node; MLN, mesenteric lymph node.

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