{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:49:33Z","timestamp":1792784973497,"version":"4.5.0"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The Alles Institute"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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-gu\u00e9rin (BCG) vaccine in autoimmune type 1 diabetes (T1D). Its administration is associated with gradual clinical improvements in human autoimmunity over a 2\u20133\u00a0year post-vaccination period. We hypothesize that those improvements, and their unusually long time course to fully materialize, are partially attributable to BCG\u2019s induction of Tregs. Here we report on a 3\u00a0year-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\u00a0years after introduction of BCG, 17 of the Foxp3 gene\u2019s 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.<\/jats:p>","DOI":"10.1038\/s41598-021-94529-2","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T06:02:59Z","timestamp":1626933779000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation"],"prefix":"10.1038","volume":"11","author":[{"given":"Ryan C.","family":"Keefe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kacie","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem M.","family":"K\u00fchtreiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise L.","family":"Faustman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"94529_CR1","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/ni1181","volume":"6","author":"Y Belkaid","year":"2005","unstructured":"Belkaid, Y. & Rouse, B. T. Natural regulatory T cells in infectious disease. Nat. Immunol. 6, 353\u2013360. https:\/\/doi.org\/10.1038\/ni1181 (2005).","journal-title":"Nat. Immunol."},{"key":"94529_CR2","doi-asserted-by":"publisher","first-page":"217","DOI":"10.3389\/fimmu.2015.00217","volume":"6","author":"MC Boer","year":"2015","unstructured":"Boer, M. C., Joosten, S. A. & Ottenhoff, T. H. Regulatory T-cells at the interface between human host and pathogens in infectious diseases and vaccination. Front. Immunol. 6, 217. https:\/\/doi.org\/10.3389\/fimmu.2015.00217 (2015).","journal-title":"Front. Immunol."},{"key":"94529_CR3","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1590\/abd1806-4841.20153311","volume":"90","author":"JNT Parente","year":"2015","unstructured":"Parente, J. N. T. et al. T regulatory cells distribution in the different clinical forms of leprosy and reactional states. Ann. Bras. Dermatol. 90, 41\u201337 (2015).","journal-title":"Ann. Bras. Dermatol."},{"key":"94529_CR4","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.3389\/fimmu.2019.02139","volume":"10","author":"P Cardona","year":"2019","unstructured":"Cardona, P. & Cardona, P. H. Regulatory T cells in Mycobacterium tuberculosis infection. Front. Immunol. 10, 2139\u20132149 (2019).","journal-title":"Front. Immunol."},{"key":"94529_CR5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002833","volume":"3","author":"B Jaron","year":"2008","unstructured":"Jaron, B., Maranghi, E., Leclerc, C. & Majlessi, L. Effect of attenuation of Treg during BCG immunization on anti-mycobacterial Th1 responses and protection against Mycobacterium tuberculosis. PLoS ONE 3, e2833. https:\/\/doi.org\/10.1371\/journal.pone.0002833 (2008).","journal-title":"PLoS ONE"},{"key":"94529_CR6","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/83713","volume":"27","author":"CL Bennett","year":"2001","unstructured":"Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20\u201321. https:\/\/doi.org\/10.1038\/83713 (2001).","journal-title":"Nat. Genet."},{"key":"94529_CR7","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1126\/science.1079490","volume":"299","author":"S Hori","year":"2003","unstructured":"Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057\u20131061. https:\/\/doi.org\/10.1126\/science.1079490 (2003).","journal-title":"Science"},{"key":"94529_CR8","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.1212\/WNL.53.7.1588","volume":"53","author":"G Ristori","year":"1999","unstructured":"Ristori, G. et al. Use of Bacille Calmette-Guerin (BCG) in multiple sclerosis. Neurology 53, 1588\u20131589 (1999).","journal-title":"Neurology"},{"key":"94529_CR9","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1007\/s00415-003-0967-6","volume":"250","author":"A Paolillo","year":"2003","unstructured":"Paolillo, A. et al. The effect of Bacille Calmette-Guerin on the evolution of new enhancing lesions to hypointense T1 lesions in relapsing remitting MS. J. Neurol. 250, 247\u2013248. https:\/\/doi.org\/10.1007\/s00415-003-0967-6 (2003).","journal-title":"J. Neurol."},{"key":"94529_CR10","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1212\/01.wnl.0000438216.93319.ab","volume":"82","author":"G Ristori","year":"2014","unstructured":"Ristori, G. et al. Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology 82, 41\u201348. https:\/\/doi.org\/10.1212\/01.wnl.0000438216.93319.ab (2014).","journal-title":"Neurology"},{"key":"94529_CR11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041756","volume":"7","author":"DL Faustman","year":"2012","unstructured":"Faustman, D. L. et al. Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes. PLoS ONE 7, e41756. https:\/\/doi.org\/10.1371\/journal.pone.0041756 (2012).","journal-title":"PLoS ONE"},{"key":"94529_CR12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41541-018-0062-8","volume":"3","author":"WM Kuhtreiber","year":"2018","unstructured":"Kuhtreiber, W. M. et al. Long-term reduction in hyperglycemia in advanced type 1 diabetes: The value of induced aerobic glycolysis with BCG vaccinations. NPJ Vaccines 3, 23. https:\/\/doi.org\/10.1038\/s41541-018-0062-8 (2018).","journal-title":"NPJ Vaccines"},{"key":"94529_CR13","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.tem.2018.11.006","volume":"30","author":"WM Kuhtreiber","year":"2019","unstructured":"Kuhtreiber, W. M. & Faustman, D. L. BCG therapy for type 1 diabetes: Restoration of balanced immunity and metabolism. Trends Endocrinol. Metab. 30, 80\u201392. https:\/\/doi.org\/10.1016\/j.tem.2018.11.006 (2019).","journal-title":"Trends Endocrinol. Metab."},{"key":"94529_CR14","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1093\/ije\/dyp307","volume":"39","author":"M El-Zein","year":"2010","unstructured":"El-Zein, M., Parent, M. E., Benedetti, A. & Rousseau, M. C. Does BCG vaccination protect against the development of childhood asthma? A systematic review and meta-analysis of epidemiological studies. Int. J. Epidemiol. 39, 469\u2013486. https:\/\/doi.org\/10.1093\/ije\/dyp307 (2010).","journal-title":"Int. J. Epidemiol."},{"key":"94529_CR15","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1016\/S1081-1206(10)61890-X","volume":"88","author":"IS Choi","year":"2002","unstructured":"Choi, I. S. & Koh, Y. I. Therapeutic effects of BCG vaccination in adult asthmatic patients: A randomized, controlled trial. Ann. Allergy Asthma Immunol. 88, 584\u2013591. https:\/\/doi.org\/10.1016\/S1081-1206(10)61890-X (2002).","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"94529_CR16","doi-asserted-by":"publisher","first-page":"5591","DOI":"10.1172\/JCI133935","volume":"130","author":"VA Koeken","year":"2020","unstructured":"Koeken, V. A. et al. BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner. J. Clin. Invest. 130, 5591\u20135602. https:\/\/doi.org\/10.1172\/JCI133935 (2020).","journal-title":"J. Clin. Invest."},{"key":"94529_CR17","doi-asserted-by":"publisher","first-page":"2562","DOI":"10.1016\/j.celrep.2016.11.011","volume":"17","author":"RJW Arts","year":"2016","unstructured":"Arts, R. J. W. et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 17, 2562\u20132571. https:\/\/doi.org\/10.1016\/j.celrep.2016.11.011 (2016).","journal-title":"Cell Rep."},{"key":"94529_CR18","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/j.cmet.2016.10.008","volume":"24","author":"RJ Arts","year":"2016","unstructured":"Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807\u2013819. https:\/\/doi.org\/10.1016\/j.cmet.2016.10.008 (2016).","journal-title":"Cell Metab."},{"key":"94529_CR19","doi-asserted-by":"publisher","first-page":"17537","DOI":"10.1073\/pnas.1202870109","volume":"109","author":"J Kleinnijenhuis","year":"2012","unstructured":"Kleinnijenhuis, J. et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl. Acad. Sci. USA 109, 17537\u201317542. https:\/\/doi.org\/10.1073\/pnas.1202870109 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"94529_CR20","doi-asserted-by":"publisher","first-page":"101085","DOI":"10.1016\/j.isci.2020.101085","volume":"23","author":"WM Kuhtreiber","year":"2020","unstructured":"Kuhtreiber, W. M. et al. BCG vaccinations upregulate myc, a central switch for improved glucose metabolism in diabetes. Science 23, 101085. https:\/\/doi.org\/10.1016\/j.isci.2020.101085 (2020).","journal-title":"Science"},{"key":"94529_CR21","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.cell.2017.12.031","volume":"172","author":"E Kaufmann","year":"2018","unstructured":"Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176\u2013190. https:\/\/doi.org\/10.1016\/j.cell.2017.12.031 (2018).","journal-title":"Cell"},{"key":"94529_CR22","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.jaci.2018.07.014","volume":"142","author":"C Schmidl","year":"2018","unstructured":"Schmidl, C., Delacher, M., Huehn, J. & Feuerer, M. Epigenetic mechanisms regulating T-cell responses. J. Allergy Clin. Immunol. 142, 728\u2013743. https:\/\/doi.org\/10.1016\/j.jaci.2018.07.014 (2018).","journal-title":"J. Allergy Clin. Immunol."},{"key":"94529_CR23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050038","volume":"5","author":"S Floess","year":"2007","unstructured":"Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38. https:\/\/doi.org\/10.1371\/journal.pbio.0050038 (2007).","journal-title":"PLoS Biol."},{"key":"94529_CR24","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.1002\/eji.200838105","volume":"38","author":"JK Polansky","year":"2008","unstructured":"Polansky, J. K. et al. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38, 1654\u20131663. https:\/\/doi.org\/10.1002\/eji.200838105 (2008).","journal-title":"Eur. J. Immunol."},{"key":"94529_CR25","doi-asserted-by":"publisher","first-page":"3153","DOI":"10.1038\/srep03153","volume":"3","author":"Y Okubo","year":"2013","unstructured":"Okubo, Y., Mera, T., Wang, L. & Faustman, D. L. Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2. Sci. Rep. 3, 3153. https:\/\/doi.org\/10.1038\/srep03153 (2013).","journal-title":"Sci. Rep."},{"key":"94529_CR26","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.2337\/db15-0572","volume":"65","author":"AM Pesenacker","year":"2016","unstructured":"Pesenacker, A. M. et al. A regulatory T-cell gene signature is a specific and sensitive biomarker to identify children with new-onset type 1 diabetes. Diabetes 65, 1031\u20131039. https:\/\/doi.org\/10.2337\/db15-0572 (2016).","journal-title":"Diabetes"},{"key":"94529_CR27","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/S0896-8411(09)90019-1","volume":"3","author":"D Faustman","year":"1990","unstructured":"Faustman, D., Eisenbarth, G., Breitmeyer, J. & Schlossman, S. Analysis of T lymphocyte subsets in all stages of diabetes. J. Autoimmun. 3, 111\u2013116 (1990).","journal-title":"J. Autoimmun."},{"key":"94529_CR28","doi-asserted-by":"publisher","first-page":"590","DOI":"10.2337\/diab.40.5.590","volume":"40","author":"D Faustman","year":"1991","unstructured":"Faustman, D., Schoenfeld, D. & Ziegler, R. T-lymphocyte changes linked to autoantibodies: Association of insulin autoantibodies with CD4+CD45R+ lymphocyte subpopulation in prediabetic subjects. Diabetes 40, 590\u2013597 (1991).","journal-title":"Diabetes"},{"key":"94529_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/cti.2015.43","volume":"5","author":"Y Okubo","year":"2016","unstructured":"Okubo, Y., Torrey, H., Butterworth, J., Zheng, H. & Faustman, D. L. Treg activation defect in type 1 diabetes: Correction with TNFR2 agonism. Clin. Transl. Immunol. 5, e56. https:\/\/doi.org\/10.1038\/cti.2015.43 (2016).","journal-title":"Clin. Transl. Immunol."},{"key":"94529_CR30","doi-asserted-by":"publisher","first-page":"465","DOI":"10.2337\/dc11-1236","volume":"35","author":"L Wang","year":"2012","unstructured":"Wang, L., Lovejoy, N. F. & Faustman, D. L. Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay. Diabetes Care 35, 465\u2013470. https:\/\/doi.org\/10.2337\/dc11-1236 (2012).","journal-title":"Diabetes Care"},{"key":"94529_CR31","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.jaut.2018.06.005","volume":"93","author":"J Ye","year":"2018","unstructured":"Ye, J. et al. Identification of loci where DNA methylation potentially mediates genetic risk of type 1 diabetes. J. Autoimmun. 93, 66\u201375. https:\/\/doi.org\/10.1016\/j.jaut.2018.06.005 (2018).","journal-title":"J. Autoimmun."},{"key":"94529_CR32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0224433","volume":"14","author":"ON Gofrit","year":"2019","unstructured":"Gofrit, O. N. et al. Bacillus Calmette-Guerin (BCG) therapy lowers the incidence of Alzheimer\u2019s disease in bladder cancer patients. PLoS ONE 14, e0224433. https:\/\/doi.org\/10.1371\/journal.pone.0224433 (2019).","journal-title":"PLoS ONE"},{"key":"94529_CR33","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1093\/infdis\/jir240","volume":"204","author":"P Aaby","year":"2011","unstructured":"Aaby, P. et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: Beneficial nonspecific effects in the neonatal period?. J. Infect. Dis. 204, 245\u2013252. https:\/\/doi.org\/10.1093\/infdis\/jir240 (2011).","journal-title":"J. Infect. Dis."},{"key":"94529_CR34","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1111\/j.1365-3156.2005.01479.x","volume":"10","author":"E Elguero","year":"2005","unstructured":"Elguero, E., Simondon, K. B., Vaugelade, J., Marra, A. & Simondon, F. Non-specific effects of vaccination on child survival? A prospective study in Senegal. Trop. Med. Int. Health 10, 956\u2013960. https:\/\/doi.org\/10.1111\/j.1365-3156.2005.01479.x (2005).","journal-title":"Trop. Med. Int. Health"},{"key":"94529_CR35","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1136\/bmj.321.7274.1435","volume":"321","author":"I Kristensen","year":"2000","unstructured":"Kristensen, I., Aaby, P. & Jensen, H. Routine vaccinations and child survival: Follow up study in Guinea-Bissau, West Africa. BMJ 321, 1435\u20131438. https:\/\/doi.org\/10.1136\/bmj.321.7274.1435 (2000).","journal-title":"BMJ"},{"key":"94529_CR36","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1186\/s12889-015-1497-8","volume":"15","author":"V Nankabirwa","year":"2015","unstructured":"Nankabirwa, V. et al. Child survival and BCG vaccination: A community based prospective cohort study in Uganda. BMC Public Health 15, 175. https:\/\/doi.org\/10.1186\/s12889-015-1497-8 (2015).","journal-title":"BMC Public Health"},{"key":"94529_CR37","doi-asserted-by":"publisher","first-page":"e73","DOI":"10.1542\/peds.2013-2218","volume":"133","author":"MG Hollm-Delgado","year":"2014","unstructured":"Hollm-Delgado, M. G., Stuart, E. A. & Black, R. E. Acute lower respiratory infection among Bacille Calmette-Guerin (BCG)-vaccinated children. Pediatrics 133, e73-81. https:\/\/doi.org\/10.1542\/peds.2013-2218 (2014).","journal-title":"Pediatrics"},{"key":"94529_CR38","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1093\/cid\/civ144","volume":"60","author":"MJ de Castro","year":"2015","unstructured":"de Castro, M. J., Pardo-Seco, J. & Martinon-Torres, F. Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis. Clin. Infect. Dis. 60, 1611\u20131619. https:\/\/doi.org\/10.1093\/cid\/civ144 (2015).","journal-title":"Clin. Infect. Dis."},{"key":"94529_CR39","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.chom.2020.05.014","volume":"28","author":"B Cirovic","year":"2020","unstructured":"Cirovic, B. et al. BCG vaccination in humans elicits trained immunity via the hematopoietic progenitor compartment. Cell Host Microbe 28, 322\u2013334. https:\/\/doi.org\/10.1016\/j.chom.2020.05.014 (2020).","journal-title":"Cell Host Microbe"},{"key":"94529_CR40","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1136\/bmj.299.6710.1259","volume":"299","author":"DP Strachan","year":"1989","unstructured":"Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259\u20131260. https:\/\/doi.org\/10.1136\/bmj.299.6710.1259 (1989).","journal-title":"BMJ"},{"key":"94529_CR41","doi-asserted-by":"crossref","unstructured":"Karaci, M. in The Value of BCG and TNF in autoimmunity (ed D. Faustman) 52\u201362 (Elsevier, 2014).","DOI":"10.1016\/B978-0-12-799964-7.00004-1"},{"key":"94529_CR42","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s11892-017-0916-x","volume":"17","author":"ST Jerram","year":"2017","unstructured":"Jerram, S. T., Dang, M. N. & Leslie, R. D. The role of epigenetics in type 1 diabetes. Curr. Diab. Rep. 17, 89. https:\/\/doi.org\/10.1007\/s11892-017-0916-x (2017).","journal-title":"Curr. Diab. Rep."},{"key":"94529_CR43","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/dmrr.2375","volume":"29","author":"MN Dang","year":"2013","unstructured":"Dang, M. N., Buzzetti, R. & Pozzilli, P. Epigenetics in auotimmune idseases with focus on type 1 diabetes. Diabetes Metab. Res. Rev. 29, 8\u201318 (2013).","journal-title":"Diabetes Metab. Res. Rev."},{"key":"94529_CR44","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13148-019-0632-2","volume":"11","author":"R Mazzone","year":"2019","unstructured":"Mazzone, R. et al. The emerging role of eptigenetics in human autoimmune disorders. Clin. Epigenet. 11, 34\u201340 (2019).","journal-title":"Clin. Epigenet."},{"key":"94529_CR45","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1080\/15592294.2020.1712814","volume":"15","author":"S Bannister","year":"2020","unstructured":"Bannister, S. et al. The emerging role of eptigenetics in the immune response to vaccination and infection: A systemic review. Epigenetics 15, 555\u2013593 (2020).","journal-title":"Epigenetics"},{"key":"94529_CR46","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1126\/science.1190689","volume":"329","author":"J Rodrigues","year":"2010","unstructured":"Rodrigues, J., Brayner, F. A., Alves, L. C., Dixit, R. & Barillas-Mury, C. Hemocyte differentiation mediates innate immune memory in Anopheles gambiae mosquitoes. Science 329, 1353\u20131355. https:\/\/doi.org\/10.1126\/science.1190689 (2010).","journal-title":"Science"},{"key":"94529_CR47","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.tplants.2011.06.004","volume":"16","author":"U Conrath","year":"2011","unstructured":"Conrath, U. Molecular aspects of defence priming. Trends Plant Sci. 16, 524\u2013531. https:\/\/doi.org\/10.1016\/j.tplants.2011.06.004 (2011).","journal-title":"Trends Plant Sci."},{"key":"94529_CR48","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1038\/nm.2087","volume":"16","author":"TB Clarke","year":"2010","unstructured":"Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat. Med. 16, 228\u2013231. https:\/\/doi.org\/10.1038\/nm.2087 (2010).","journal-title":"Nat. Med."},{"key":"94529_CR49","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.coph.2018.04.007","volume":"41","author":"VP Mourits","year":"2018","unstructured":"Mourits, V. P., Wijkmans, J. C., Joosten, L. A. & Netea, M. G. Trained immunity as a novel therapeutic strategy. Curr. Opin. Pharmacol. 41, 52\u201358. https:\/\/doi.org\/10.1016\/j.coph.2018.04.007 (2018).","journal-title":"Curr. Opin. Pharmacol."},{"key":"94529_CR50","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fimmu.2019.00043","volume":"10","author":"M Romano","year":"2019","unstructured":"Romano, M., Fanelli, G., Albany, C. J., Giganti, G. & Lombardi, G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front. Immunol. 10, 43. https:\/\/doi.org\/10.3389\/fimmu.2019.00043 (2019).","journal-title":"Front. Immunol."},{"key":"94529_CR51","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.cbpa.2014.09.006","volume":"23","author":"RA Rosalia","year":"2014","unstructured":"Rosalia, R. A., Arenas-Ramirez, N., Bouchaud, G., Raeber, M. E. & Boyman, O. Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer. Curr. Opin. Chem. Biol. 23, 39\u201346. https:\/\/doi.org\/10.1016\/j.cbpa.2014.09.006 (2014).","journal-title":"Curr. Opin. Chem. Biol."},{"key":"94529_CR52","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1126\/science.3895437","volume":"229","author":"B Beutler","year":"1985","unstructured":"Beutler, B., Milsark, I. W. & Cerami, A. C. Passive immunization against cachectin\/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229, 869\u2013871. https:\/\/doi.org\/10.1126\/science.3895437 (1985).","journal-title":"Science"},{"key":"94529_CR53","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1172\/JCI45005","volume":"124","author":"R Keeton","year":"2014","unstructured":"Keeton, R. et al. Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis. J. Clin. Invest. 124, 1537\u20131551. https:\/\/doi.org\/10.1172\/JCI45005 (2014).","journal-title":"J. Clin. Invest."},{"key":"94529_CR54","doi-asserted-by":"publisher","first-page":"594","DOI":"10.3389\/fimmu.2018.00594","volume":"9","author":"H Zou","year":"2018","unstructured":"Zou, H., Li, R., Hu, H., Hu, Y. & Chen, X. Modulation of regulatory T cell activity by TNF receptor type II-targeting pharmacological agents. Front. Immunol. 9, 594. https:\/\/doi.org\/10.3389\/fimmu.2018.00594 (2018).","journal-title":"Front. Immunol."},{"key":"94529_CR55","doi-asserted-by":"publisher","first-page":"9600","DOI":"10.1126\/scisignal.aba9600","volume":"13","author":"H Torrey","year":"2020","unstructured":"Torrey, H. et al. A novel TNFR2 agonist antibody expands highly potent regulatory T cells. Sci. Signal 13, 9600. https:\/\/doi.org\/10.1126\/scisignal.aba9600 (2020).","journal-title":"Sci. Signal"},{"key":"94529_CR56","doi-asserted-by":"publisher","DOI":"10.1101\/1638072","author":"G Marodon","year":"2020","unstructured":"Marodon, G. In Silico characterization of a \u201cuniversal\u201d Treg signature reveals the pro enkephalin gene as a novel Treg marker. BioRxiv https:\/\/doi.org\/10.1101\/1638072 (2020).","journal-title":"BioRxiv"},{"key":"94529_CR57","doi-asserted-by":"publisher","first-page":"R54","DOI":"10.1186\/gb-2006-7-7-r54","volume":"7","author":"S Pfoertner","year":"2006","unstructured":"Pfoertner, S. et al. Signatures of human regulatory T cells: An encounter with old friends and new players. Genome Biol. 7, R54. https:\/\/doi.org\/10.1186\/gb-2006-7-7-r54 (2006).","journal-title":"Genome Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-94529-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-94529-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-94529-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T06:41:54Z","timestamp":1670049714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-94529-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,22]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["94529"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-94529-2","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.740541769.793588168","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,22]]},"assertion":[{"value":"10 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14933"}}