e. to link the changes in gene expression to phenotypic changes and (1) to determine whether differential gene expression really results in an observable altered phenotype and (2) to determine whether this differential gene expression and the resulting phenotype are attributable to

the stress conditions applied. I wish to thank BOF-UGent, the Fund for Scientific Research-Flanders and Cystic Fibrosis Foundation Therapeutics Inc. for financial support. I also wish to thank colleagues and coworkers (past and present) for their collaboration and support. I apologize to the colleagues whose work I was not able to cite due to space constraints. “
“TNF is a pleiotropic cytokine with intriguing biphasic pro-inflammatory and anti-inflammatory effects. Our previous studies demonstrated that https://www.selleckchem.com/products/PD-0332991.html TNF up-regulated FoxP3 expression and activated and expanded CD4+FoxP3+ regulatory T cells (Tregs) via TNFR2. Furthermore, TNFR2-expressing learn more Tregs exhibited maximal suppressive activity. In this study, we show that TNF, in concert

with IL-2, preferentially up-regulated mRNA and surface expression of TNFR2, 4-1BB and OX40 on Tregs. Agonistic antibodies against 4-1BB and OX40 also induced the proliferation of suppressive Tregs. Thus, TNF amplifies its stimulatory effect on Tregs by inducing TNF receptor superfamily (TNFRSF) members. In addition, administration of neutralizing anti-TNF Ab blocked LPS-induced expansion of splenic Tregs and up-regulation of TNFR2, OX40 and 4-1BB receptors on Tregs in vivo, indicating that the expansion of Tregs expressing these co-stimulatory TNFRSF members in response to LPS is mediated by TNF. Altogether, our novel data indicate that TNF preferentially up-regulates TNFR2

on Tregs, and this is amplified by the stimulation of 4-1BB and OX40, resulting in the optimal activation of Tregs and augmented attenuation of excessive inflammatory responses. CD4+FoxP3+ regulatory T cells Phospholipase D1 (Tregs) comprise only a minor fraction (∼10%) of peripheral CD4+ T cells, but play a critical role in the establishment and maintenance of immunological tolerance to self-antigens as well as to foreign antigens 1, 2. Certain cytokine receptors preferentially expressed by Tregs not only serve as surface markers for the identification of Tregs but also promote the function of Tregs. CD25, the α chain of the IL-2 receptor, is the prototype of such cytokine receptors 1, 2. Our previous studies indicate that TNFR2 is an important cytokine receptor preferentially expressed by the highly suppressive human and mouse Tregs 3–5. TNFR2 is one of two receptors transducing the biological function of TNF, a pleiotropic cytokine that is a major participant in the initiation and orchestration of inflammation and immunity 6. TNFR2 expression is restricted to certain T-cell subpopulations 6, and acts as a co-stimulator for antigen-driven T-cell responses 7.