BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation

Abstract Induction of immunosuppressive T-regulatory cells (Tregs) is a desirable goal in autoimmunity, and perhaps other immune diseases of activation. One promising avenue is with the bacille-calmette-guérin (BCG) vaccine in autoimmune type 1 diabetes (T1D). Its administration is associated with g...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ryan C. Keefe, Hiroyuki Takahashi, Lisa Tran, Kacie Nelson, Nathan Ng, Willem M. Kühtreiber, Denise L. Faustman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/09f73d65921c45aab18448f13edbdcdf
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:09f73d65921c45aab18448f13edbdcdf
record_format	dspace
spelling	oai:doaj.org-article:09f73d65921c45aab18448f13edbdcdf2021-12-02T16:26:37ZBCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation10.1038/s41598-021-94529-22045-2322https://doaj.org/article/09f73d65921c45aab18448f13edbdcdf2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94529-2https://doaj.org/toc/2045-2322Abstract Induction of immunosuppressive T-regulatory cells (Tregs) is a desirable goal in autoimmunity, and perhaps other immune diseases of activation. One promising avenue is with the bacille-calmette-guérin (BCG) vaccine in autoimmune type 1 diabetes (T1D). Its administration is associated with gradual clinical improvements in human autoimmunity over a 2–3 year post-vaccination period. We hypothesize that those improvements, and their unusually long time course to fully materialize, are partially attributable to BCG’s induction of Tregs. Here we report on a 3 year-long longitudinal cohort of T1Ds and examine the mechanism by which Treg induction occurs. Using the Human Infinium Methylation EPIC Bead Chip, we show that BCG vaccination is associated with gradual demethylation of most of 11 signature genes expressed in highly potent Tregs: Foxp3, TNFRSF18, CD25, IKZF2, IKZF4, CTLA4, TNFR2, CD62L, Fas, CD45 and IL2; nine of these 11 genes, by year 3, became demethylated at the majority of CpG sites. The Foxp3 gene was studied in depth. At baseline Foxp3 was over-methylated compared to non-diabetic controls; 3 years after introduction of BCG, 17 of the Foxp3 gene’s 22 CpG sites became significantly demethylated including the critical TSDR region. Corresponding mRNA, Treg expansion and clinical improvement supported the significance of the epigenetic DNA changes. Taken together, the findings suggest that BCG has systemic impact on the T cells of the adaptive immune system, and restores immune balance through Treg induction.Ryan C. KeefeHiroyuki TakahashiLisa TranKacie NelsonNathan NgWillem M. KühtreiberDenise L. FaustmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ryan C. Keefe Hiroyuki Takahashi Lisa Tran Kacie Nelson Nathan Ng Willem M. Kühtreiber Denise L. Faustman BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation
description	Abstract Induction of immunosuppressive T-regulatory cells (Tregs) is a desirable goal in autoimmunity, and perhaps other immune diseases of activation. One promising avenue is with the bacille-calmette-guérin (BCG) vaccine in autoimmune type 1 diabetes (T1D). Its administration is associated with gradual clinical improvements in human autoimmunity over a 2–3 year post-vaccination period. We hypothesize that those improvements, and their unusually long time course to fully materialize, are partially attributable to BCG’s induction of Tregs. Here we report on a 3 year-long longitudinal cohort of T1Ds and examine the mechanism by which Treg induction occurs. Using the Human Infinium Methylation EPIC Bead Chip, we show that BCG vaccination is associated with gradual demethylation of most of 11 signature genes expressed in highly potent Tregs: Foxp3, TNFRSF18, CD25, IKZF2, IKZF4, CTLA4, TNFR2, CD62L, Fas, CD45 and IL2; nine of these 11 genes, by year 3, became demethylated at the majority of CpG sites. The Foxp3 gene was studied in depth. At baseline Foxp3 was over-methylated compared to non-diabetic controls; 3 years after introduction of BCG, 17 of the Foxp3 gene’s 22 CpG sites became significantly demethylated including the critical TSDR region. Corresponding mRNA, Treg expansion and clinical improvement supported the significance of the epigenetic DNA changes. Taken together, the findings suggest that BCG has systemic impact on the T cells of the adaptive immune system, and restores immune balance through Treg induction.
format	article
author	Ryan C. Keefe Hiroyuki Takahashi Lisa Tran Kacie Nelson Nathan Ng Willem M. Kühtreiber Denise L. Faustman
author_facet	Ryan C. Keefe Hiroyuki Takahashi Lisa Tran Kacie Nelson Nathan Ng Willem M. Kühtreiber Denise L. Faustman
author_sort	Ryan C. Keefe
title	BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation
title_short	BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation
title_full	BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation
title_fullStr	BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation
title_full_unstemmed	BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation
title_sort	bcg therapy is associated with long-term, durable induction of treg signature genes by epigenetic modulation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/09f73d65921c45aab18448f13edbdcdf
work_keys_str_mv	AT ryanckeefe bcgtherapyisassociatedwithlongtermdurableinductionoftregsignaturegenesbyepigeneticmodulation AT hiroyukitakahashi bcgtherapyisassociatedwithlongtermdurableinductionoftregsignaturegenesbyepigeneticmodulation AT lisatran bcgtherapyisassociatedwithlongtermdurableinductionoftregsignaturegenesbyepigeneticmodulation AT kacienelson bcgtherapyisassociatedwithlongtermdurableinductionoftregsignaturegenesbyepigeneticmodulation AT nathanng bcgtherapyisassociatedwithlongtermdurableinductionoftregsignaturegenesbyepigeneticmodulation AT willemmkuhtreiber bcgtherapyisassociatedwithlongtermdurableinductionoftregsignaturegenesbyepigeneticmodulation AT deniselfaustman bcgtherapyisassociatedwithlongtermdurableinductionoftregsignaturegenesbyepigeneticmodulation
_version_	1718383974740393984

BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation

Ejemplares similares