Antitumor Immunity Graft-versus-Host Disease and Generation: Implications in Regulatory Lymphocyte + FOXP3 (original) (raw)

Impaired T Cell Receptor Signaling in Foxp3+ CD4 T Cells

Annals of the New York Academy of Sciences, 2007

Dominant tolerance to autoantigens is primarily achieved through the action of the CD4 + CD25 + Foxp3 + subset of T cells, which have the capability of suppressing autoreactive T cells that have escaped deletion during thymic selection. The essential role of the forkhead/winged-helix transcription factor Foxp3 in the development and function of these cells has been well documented. What is less clear is the role of Foxp3 in the altered TCR signaling that is seen in Tregs. We have used a Foxp3 transgenic mouse line to demonstrate that Foxp3 expression correlates with attenuated TCR signaling, and that the deficit in Foxp3-transgenic CD4 T cells, as well as in CD4 + CD25 + Tregs, affects multiple biochemical pathways.

De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR

Journal of Leukocyte Biology, 2008

Although regulatory CD4؉CD25؉ forkhead box p3؉ (Foxp3؉) T cells (Tregs) are generally thought to arise in the thymus as a separate lineage of CD4 T cells, they can also be induced de novo in the periphery. Peripheral development of Tregs from naïve T cells is favored by low-intensity activation and absence of inflammation. We show here that absence of CD28 costimulation results in a modest decrease in activation of naïve, antigen-specific CD4 T cells under noninflammatory conditions and benefits their initial Foxp3 induction. However, expression of Foxp3 following T cell activation without CD28 costimulation remains sensitive to the antigen dose. Furthermore, basal CD28 costimulation is critical for survival of the induced Foxp3؉ CD4 T cells, and their accumulation is abrogated in the absence of CD28. In contrast, pharmacologic blockade of mammalian target of rapamycin enhances lasting induction of Tregs, irrespective of the initial antigen dose used to activate the antigen-specific T cells. This finding may have important practical, clinical implication in development of tolerance protocols. J. Leukoc. Biol. 83: 000 -000; 2008.