Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 49, Pages 19414-19419Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0807743105
Keywords
autoimmunity; T cell help; T cell homeostasis
Categories
Funding
- Ligue Contre le Cancer-Region Languedoc-Roussillon
- Institut National de la Sante et de la Recherche Medicale
- Contrat d'interface with the Centre Hospitalier Universitaire de Amiens
- Contrat d'interface with the Centre Hospitalier Universitaire de Montellier
- European Community [LSHC-CT-2005-018914]
- Association pour laRecherchecontre le Cancer
- Association de langue francaise pour l'etude du diabete et des maladies metaboliques
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The onset of autoimmunity in experimental rodent models and patients frequently correlates with a lymphopenic state. In this condition, the immune system has evolved compensatory homeostatic mechanisms that induce quiescent naive T cells to proliferate and differentiate into memory-like lymphocytes even in the apparent absence of antigenic stimulation. Because memory T cells have less stringent requirements for activation than naive cells, we hypothesized that autoreactive T cells that arrive to secondary lymphoid organs in a lymphopenic environment could differentiate and bypass the mechanisms of peripheral tolerance such as those mediated by self-antigen cross-presentation. Here, we show that lymphopenia-driven proliferation and differentiation of potentially autoreactive CD8(+) T cells into memory-like cells is not sufficient to induce self-reactivity against a pancreatic antigen. Induction of an organ-specific autoimmunity required antigen-specific CD4(+) T cell help. Notably, we found that this function could be accomplished by memory-like CD4(+) T cells generated in vivo through lymphopenia-induced proliferation. These helper cells promoted the further differentiation of memory-like CD8(+) T cells into effectors in response to antigen cross-presentation, resulting in their migration to the tissue of antigen expression where autoimmunity ensued. Thus, the cooperation of self-reactive memory-like CD4(+) and CD8(+) T cells under lymphopenic conditions overcomes cross-tolerance resulting in autoimmunity.
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