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Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2999-3004. doi: 10.1073/pnas.0712135105. Epub 2008 Feb 14.

CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity.

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The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.


There are many inhibitory mechanisms that function at the cellular and molecular levels to maintain tolerance. Despite this, self-reactive clones escape regulatory mechanisms and cause autoimmunity in certain circumstances. We hypothesized that the same mechanisms that permit T cells to expand during homeostatic proliferation may inadvertently promote autoimmunity under certain conditions. One major homeostatic cytokine is IL-7, and studies have linked it or its receptor to the development of multiple sclerosis and other autoimmune diseases. We show in a model of beta-islet cell self-reactivity that the transfer of activated autoreactive CD4 T cells can prime and expand endogenous autoreactive CD8 T cells in a CD28- and CD40-dependent manner through the licensing of dendritic cells. Despite this, mice do not develop diabetes. However, the provision of exogenous IL-7 or the physiological production of IL-7 associated with lymphopenia was able to profoundly promote the expansion of self-reactive clones even in the presence of regulatory T cells. Autoimmune diabetes rapidly ensued with CD4 help and the subsequent activation of CD8 T cells, which contributed to disease progression. With the advent of many biologicals targeting TNFalpha, IL-6, and IL-1 and their effective use in the treatment of autoimmune diseases, we propose that IL-7 and its receptor may be promising targets for biological agents in the treatment of autoimmunity.

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