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PLoS One. 2010 Sep 10;5(9):e12659. doi: 10.1371/journal.pone.0012659.

IL-2 mediates CD4+ T cell help in the breakdown of memory-like CD8+ T cell tolerance under lymphopenic conditions.

Author information

1
Institut de Génétique Moléculaire de Montpellier, UMR 5535 Centre National de la Recherche Scientifique, Université Montpellier 2 and Université Montpellier 1, Montpellier, France.

Abstract

BACKGROUND:

Lymphopenia results in the proliferation and differentiation of naïve T cells into memory-like cells in the apparent absence of antigenic stimulation. This response, at least in part due to a greater availability of cytokines, is thought to promote anti-self responses. Although potentially autoreactive memory-like CD8(+) T cells generated in a lymphopenic environment are subject to the mechanisms of peripheral tolerance, they can induce autoimmunity in the presence of antigen-specific memory-like CD4(+) T helper cells.

METHODOLOGY/PRINCIPAL FINDINGS:

Here, we studied the mechanisms underlying CD4 help under lymphopenic conditions in transgenic mice expressing a model antigen in the beta cells of the pancreas. Surprisingly, we found that the self-reactivity mediated by the cooperation of memory-like CD8(+) and CD4(+) T cells was not abrogated by CD40L blockade. In contrast, treatment with anti-IL-2 antibodies inhibited the onset of autoimmunity. IL-2 neutralization prevented the CD4-mediated differentiation of memory-like CD8(+) T cells into pathogenic effectors in response to self-antigen cross-presentation. Furthermore, in the absence of helper cells, induction of IL-2 signaling by an IL-2 immune complex was sufficient to promote memory-like CD8(+) T cell self-reactivity.

CONCLUSIONS/SIGNIFICANCE:

IL-2 mediates the cooperation of memory-like CD4(+) and CD8(+) T cells in the breakdown of cross-tolerance, resulting in effector cytotoxic T lymphocyte differentiation and the induction of autoimmune disease.

PMID:
20856822
PMCID:
PMC2939396
DOI:
10.1371/journal.pone.0012659
[Indexed for MEDLINE]
Free PMC Article

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