Suppression by TFRcells leads to durable and selective inhibition of B cell effector function.
Follicular regulatory T cells (TFRcells) inhibit follicular helper T cell (TFHcell)-mediated antibody production. The mechanisms by which TFRcells exert their key immunoregulatory functions are largely unknown. Here we found that TFRcells induced a distinct suppressive state in TFHcells and B cells, in which effector transcriptional signatures were maintained but key effector molecules and metabolic pathways were suppressed. The suppression of B cell antibody production and metabolism by TFRcells was durable and persisted even in the absence of TFRcells. This durable suppression was due in part to epigenetic changes. The cytokine IL-21 was able to overcome TFRcell-mediated suppression and inhibited TFRcells and stimulated B cells. By determining mechanisms of TFRcell-mediated suppression, we have identified methods for modulating the function of TFRcells and antibody production.
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.|Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Peter T
PT
Sage
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Noga
N
Ron-Harel
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.|Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Vikram R
VR
Juneja
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Debattama R
http://orcid.org/0000-0002-0947-8284
DR
Sen
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.|Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Seth
S
Maleri
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Waradon
W
Sungnak
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Vijay K
VK
Kuchroo
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
W Nicholas
WN
Haining
FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.
Nicolas
N
Chevrier
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Marcia
M
Haigis
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.|Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Arlene H
AH
Sharpe
D000818:Animals; D000917:Antibody Formation; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology*; D007108:Immune Tolerance; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000098546:Interleukin-21
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D000098546:Interleukin-21
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