TY - JOUR
T1 - Transcription factor Foxp1 regulates Foxp3 chromatin binding and coordinates regulatory T cell function
AU - Konopacki, Catherine
AU - Pritykin, Yuri
AU - Rubtsov, Yury
AU - Leslie, Christina S.
AU - Rudensky, Alexander Y.
N1 - Funding Information:
We thank the Memorial Sloan Kettering Cancer Center (MSKCC) integrated genomics operation for sequencing RNA-seq and ChIP-seq libraries and preprocessing data. We thank A.C. Scott and D. Tran for help with tissue lymphocyte isolation and experiment optimization and all members of the A.Y. Rudensky laboratory for helpful discussions and technical assistance. This study was supported by NIH grants R37 AI034206 (A.Y.R.), P30 CA008748 (A.Y.R.) and U01 HG007893 (A.Y.R. and C.S.L.), as well as the Hilton–Ludwig Cancer Prevention Initiative funded by the Conrad N. Hilton Foundation and Ludwig Cancer Research (A.Y.R.). A.Y.R. is an investigator with the Howard Hughes Medical Institute.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Regulatory T cells (T reg cells), whose differentiation and function are controlled by transcription factor Foxp3, express the closely related family member Foxp1. Here we explored Foxp1 function in T reg cells. We found that a large number of Foxp3-bound genomic sites in T reg cells were occupied by Foxp1 in both T reg cells and conventional T cells (T conv cells). In T reg cells, Foxp1 markedly increased Foxp3 binding to these sites. Foxp1 deficiency in T reg cells resulted in their impaired function and competitive fitness, associated with markedly reduced CD25 expression and interleukin-2 (IL-2) responsiveness, diminished CTLA-4 expression and increased SATB1 expression. The characteristic expression patterns of CD25, Foxp3 and CTLA-4 in T reg cells were fully or partially rescued by strong IL-2 signaling. Our studies suggest that Foxp1 serves an essential non-redundant function in T reg cells by enforcing Foxp3-mediated regulation of gene expression and enabling efficient IL-2 signaling in these cells.
AB - Regulatory T cells (T reg cells), whose differentiation and function are controlled by transcription factor Foxp3, express the closely related family member Foxp1. Here we explored Foxp1 function in T reg cells. We found that a large number of Foxp3-bound genomic sites in T reg cells were occupied by Foxp1 in both T reg cells and conventional T cells (T conv cells). In T reg cells, Foxp1 markedly increased Foxp3 binding to these sites. Foxp1 deficiency in T reg cells resulted in their impaired function and competitive fitness, associated with markedly reduced CD25 expression and interleukin-2 (IL-2) responsiveness, diminished CTLA-4 expression and increased SATB1 expression. The characteristic expression patterns of CD25, Foxp3 and CTLA-4 in T reg cells were fully or partially rescued by strong IL-2 signaling. Our studies suggest that Foxp1 serves an essential non-redundant function in T reg cells by enforcing Foxp3-mediated regulation of gene expression and enabling efficient IL-2 signaling in these cells.
UR - http://www.scopus.com/inward/record.url?scp=85059939011&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059939011&partnerID=8YFLogxK
U2 - 10.1038/s41590-018-0291-z
DO - 10.1038/s41590-018-0291-z
M3 - Article
C2 - 30643266
AN - SCOPUS:85059939011
SN - 1529-2908
VL - 20
SP - 232
EP - 242
JO - Nature Immunology
JF - Nature Immunology
IS - 2
ER -