Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response.
Stable Foxp3 expression is crucial for regulatory T (Treg) cell function. We observed that antigen-driven activation and inflammation in the CNS promoted Foxp3 instability selectively in the autoreactive Treg cells that expressed high amounts of Foxp3 before experimental autoimmune encephalitis induction. Treg cells with a demethylated Treg-cell-specific demethylated region in the Foxp3 locus downregulated Foxp3 transcription in the inflamed CNS during the induction phase of the response. Stable Foxp3 expression returned at the population level with the resolution of inflammation or was rescued by IL-2-anti-IL-2 complex treatment during the antigen priming phase. Thus, a subset of fully committed self-antigen-specific Treg cells lost Foxp3 expression during an inflammatory autoimmune response and might be involved in inadequate control of autoimmunity. These results have important implications for Treg cell therapies and give insights into the dynamics of the Treg cell network during autoreactive CD4(+) T cell effector responses in vivo.
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Samantha L
SL
Bailey-Bucktrout
Marc
M
Martinez-Llordella
Xuyu
X
Zhou
Bryan
B
Anthony
Wendy
W
Rosenthal
Herve
H
Luche
Hans J
HJ
Fehling
Jeffrey A
JA
Bluestone
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019070:Cell Lineage; D002490:Central Nervous System / Q000276:immunology; D019175:DNA Methylation; D015536:Down-Regulation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology*; D017930:Genes, Reporter; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012045:Regulatory Sequences, Nucleic Acid; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C585905:MOG(38-49) peptide, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins