Cell-intrinsic NF-?B activation is critical for the development of natural regulatory T cells in mice.

ABSTRACT:

Background

Naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells develop in the thymus and represent a mature T cell subpopulation critically involved in maintaining peripheral tolerance. The differentiation of Treg cells in the thymus requires T cell receptor (TCR)/CD28 stimulation along with cytokine-promoted Foxp3 induction. TCR-mediated nuclear factor kappa B (NF-?B) activation seems to be involved in differentiation of Treg cells because deletion of components of the NF-?B signaling pathway, as well as of NF-?B transcription factors, leads to markedly decreased Treg cell numbers in thymus and periphery.

Methodology/principal findings

To investigate if Treg cell-intrinsic NF-?B activation is required for thymic development and peripheral homeostasis of Treg cells we used transgenic (Tg) mice with thymocyte-specific expression of a stable I?B? mutant to inhibit NF-?B activation solely within the T cell lineage. Here we show that Treg cell-intrinsic NF-?B activation is important for the generation of cytokine-responsive Foxp3(-) thymic Treg precursors and their further differentiation into mature Treg cells. Treg cell development could neither be completely rescued by the addition of exogenous Interleukin 2 (IL-2) nor by the presence of wild-type derived cells in adoptive transfer experiments. However, peripheral NF-?B activation appears to be required for IL-2 production by conventional T cells, thereby participating in Treg cell homeostasis. Moreover, pharmacological NF-?B inhibition via the I?B kinase ? (IKK?) inhibitor AS602868 led to markedly diminished thymic and peripheral Treg cell frequencies.

Conclusion/significance

Our results indicate that Treg cell-intrinsic NF-?B activation is essential for thymic Treg cell differentiation, and further suggest pharmacological NF-?B inhibition as a potential therapeutic approach for manipulating this process.

SUBMITTER: Guckel E 

PROVIDER: S-EPMC3097234 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature