Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor.
Naturally derived regulatory T (Treg) cells are characterized by stable expression of the transcription factor Foxp3 and characteristic epigenetic imprinting at the Foxp3 gene locus. Here, we found that enhancing nuclear factor (NF)-kappaB activity via a constitutive active inhibitor of kappaB kinase beta (IKKbeta) transgene in T cells led to increased number of Foxp3(+) cells in the thymus and can rescue Foxp3 expression in thymocytes deficient in other pleiotropic signaling molecules. Enhancing the signal strength of the NF-kappaB pathway also induced Foxp3 expression in otherwise conventionally selected T cells. NF-kappaB directly promoted the transcription of Foxp3, and upon T cell receptor (TCR) stimulation, c-Rel, a NF-kappaB family member, bound to Foxp3 enhancer region, which is specifically demethylated in natural Treg cells. Hence, NF-kappaB signaling pathway is a key regulator of Foxp3 expression during natural Treg cell development.
Long
Meixiao
M
Department of Immunobiology and Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
Park
Sung-Gyoo
SG
Strickland
Ian
I
Hayden
Matthew S
MS
Ghosh
Sankar
S
D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018392:Genomic Imprinting; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D000099151:MAP Kinase Kinase Kinase 7
D053468:CARD Signaling Adaptor Proteins; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D020672:I-kappa B Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D000099151:MAP Kinase Kinase Kinase 7; C496467:Card11 protein, mouse; C498833:Foxp3 protein, mouse; C064658:RAG-1 protein