CD28 costimulation regulates FOXP3 in a RelA/NF-κB-dependent mechanism

Marzia Soligo; Cristina Camperio; Silvana Caristi; Cristiano Scottà; Paola Del Porto; Antonio Costanzo; Pierre-Yves Mantel; Carsten B Schmidt-Weber; Enza Piccolella

doi:10.1002/eji.201040712

CD28 costimulation regulates FOXP3 in a RelA/NF-κB-dependent mechanism

Eur J Immunol. 2011 Feb;41(2):503-13. doi: 10.1002/eji.201040712. Epub 2011 Jan 11.

Authors

Marzia Soligo¹, Cristina Camperio, Silvana Caristi, Cristiano Scottà, Paola Del Porto, Antonio Costanzo, Pierre-Yves Mantel, Carsten B Schmidt-Weber, Enza Piccolella

Affiliation

¹ Department of Biology and Biotechnology C. Darwin, University Sapienza of Rome, Italy.

PMID: 21268019
DOI: 10.1002/eji.201040712

Abstract

The molecular mechanisms whereby CD28 alone or associated with TCR can regulate FOXP3 expression are not understood, although the importance of CD28 as a pivotal regulator of CD4(+) CD25(+) FOXP3(+) T cells is well recognized. We previously demonstrated that unique CD28-induced, NF-κB-dependent signals were sufficient to activate FOXP3 transcription in human CD4(+) CD25(-) T cells; however, the exact mechanisms are currently unknown. In this study, we have identified novel κB-binding sites on FOXP3 gene and demonstrated that CD28 signals mediated FOXP3 trans activation by nuclear translocation of RelA/NF-κB and not of c-Rel. The occupancy of FOXP3 κB-binding sites by RelA dimers that correlated with histone acetylation and recruitment of Pol II were required both to initiate FOXP3 transcription and to control the promoter occupancy by NFAT. Interestingly, knockdown of RelA in CD4(+) CD25(-) T cells stimulated through TCR and CD28 significantly affected FOXP3 expression, confirming that also the transcriptional activation of FOXP3 gene by TCR in the presence of CD28-costimulatory signals is RelA-dependent. In conclusion, these data suggest a new mechanism by which FOXP3 is activated and supports the critical role of CD28 in the regulation of peripheral tolerance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Antibodies / immunology
Antibodies / pharmacology
B7-1 Antigen / immunology
B7-1 Antigen / metabolism
CD28 Antigens / immunology*
CD3 Complex / immunology
Cyclosporine / pharmacology
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
HEK293 Cells
Histones / metabolism
Humans
Interleukin-2 Receptor alpha Subunit / metabolism
L Cells / immunology
L Cells / metabolism
Lymphocyte Activation / drug effects
Lymphocyte Activation / physiology*
Mice
NF-kappa B / antagonists & inhibitors
NF-kappa B / metabolism*
NFATC Transcription Factors / antagonists & inhibitors
NFATC Transcription Factors / genetics
NFATC Transcription Factors / metabolism
Promoter Regions, Genetic / genetics
Protein Binding / genetics
RNA, Small Interfering / genetics
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism*
Tetradecanoylphorbol Acetate / pharmacology
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism*
Transcriptional Activation / drug effects
Transcriptional Activation / physiology
Transfection

Substances

Antibodies
B7-1 Antigen
CD28 Antigens
CD3 Complex
FOXP3 protein, human
Forkhead Transcription Factors
Histones
IL2RA protein, human
Interleukin-2 Receptor alpha Subunit
NF-kappa B
NFATC Transcription Factors
RELA protein, human
RNA, Small Interfering
Transcription Factor RelA
Cyclosporine
Tetradecanoylphorbol Acetate