Study of peripheral self-tolerance mechanisms in transgenic mouse models

• Auteur / Autrice : Fay Magnusson
• Direction : Roland Liblau, Khashayarsha Khazaie
• Type : Thèse de doctorat
• Discipline(s) : Immunologie
• Date : Soutenance en 2008
• Etablissement(s) : Toulouse 3

Mots clés

Mots clés contrôlés

Souris de laboratoire

Lymphocytes T

Thymus

Régulation génétique

Tolérance immunitaire

Cellules stromales médullaires

Autoimmunité

Antigènes

Mots clés libres

Auto-immunité

Lymphocytes T

Tolérance immunitaire

Maladies inflammatoires de l'intestin

Cellule stromale ganglionnaire

Lymphocyte T regulateur

Thymus

Résumé

Le système immunitaire joue un rôle important dans le maintien de l'intégrité du corps humain puisqu'il le protège contre diverses infections virales et bacteriennes, tout en lui attribuant tolérance envers les antigènes du soi. Plusieurs mécanismes de tolérance au soi nous protègent des maladies auto-immunes. Dans le contexte de la tolérance périphérique et à l'aide de modèles murins transgéniques, nous avons étudié le rôle de la délétion via présentation directe d'antigènes par les cellules stromales de ganglions lymphatiques, dans les maladies inflammatoires de l'intestin causées par les lymphocytes T CD4 ou CD8. Nous avons également etudié la génération thymique de cellules T régulatrices (Tregs) spécifiques d'un néo-antigène du soi, et le mécanisme de la suppression des Tregs par comparaison de puces à ADN provenant de lymphocytes T CD8 régulés ou non par des Tregs.

Several mechanisms of peripheral self-tolerance, including CD4+ CD25+ Foxp3+ regulatory T cells (Tregs), cross-presentation by dendritic cells (DCs) and the newly identified direct presentation of antigen by lymph node (LN) stromal cells, contribute to protecting our bodies and animals from self-damaging autoimmune diseases. We first sought to determine the relative contribution of antigen-specific CD8 and CD4 T cells to intestinal autoimmunity. To this end, we studied autoimmune targeting of an ectopic antigen expressed by enteric glial cells, in transgenic mouse models. We found that direct presentation of antigen by LN stromal cells caused the activation induced cell death of specific CD8 T cells. In contrast, conventional CD4 T cells were not affected by this mechanism of tolerance and their targeting of enteric glial cells produced lethal intestinal autoimmunity. Thus, we conclude that in our mouse model, this novel mechanism of peripheral tolerance preferentially protects against CD8 T cell intestinal autoimmunity. Furthermore, we have established a new model of antigen-specific CD4 T cell-mediated small intestine autoimmunity. To determine the relative contribution of Tregs, DCs and LN stromal cells for protection against autoimmunity, we sought conditions that make adoptively transferred naïve conventional CD8 T cells autoaggressive. Depletion of Treg cells, non-specific activation of the T cells through their lymphopenic expansion, and inhibition of TGF-beta receptor signaling in T cells achieved autoimmunity. The CD8 T cells caused multi-organ autoimmunity, but the intestine was not affected. Since insensitivity to TGF-beta rendered the T cells resistant to deletion through cross-presentation but not direct presentation of antigen, we conclude that the former was the critical mechanism determining the outcome of the immune response. Furthermore, these observations leave the possibility open that direct presentation by LN stromal cells preferentially protects the intestine against CD8 T cell attack, although other mechanisms of mucosal tolerance may be also involved. Altogether, these results provide new insights into the mechanisms of peripheral CD8 T cell tolerance, and tissue specific autoimmunity. A thorough understanding of these events is necessary to allow effective therapeutic intervention in autoimmunity and cancer.