Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells.
Follicular T helper (Tfh) cells provide critical help to B cells for germinal center (GC) formation. Mutations affecting SLAM-associated protein (SAP) prevent GC formation because of defective T cell-B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent "Tfh-like" cells that expressed interleukin-21, Tfh cell markers, and Bcl6 and rescued GC formation in SAP-deficient hosts better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wild-type, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, Th1, Th2, and Th17 cells could be reprogrammed to obtain Tfh cell characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3, and Rorc in Tfh-like and ex vivo Tfh cells and on Bcl6 in non-Tfh cells, supporting the concept of plasticity between Tfh and other Th cell populations.
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Kristina T
KT
Lu
Yuka
Y
Kanno
Jennifer L
JL
Cannons
Robin
R
Handon
Paul
P
Bible
Abdel G
AG
Elkahloun
Stacie M
SM
Anderson
Lai
L
Wei
Hongwei
H
Sun
John J
JJ
O'Shea
Pamela L
PL
Schwartzberg
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology; D044127:Epigenesis, Genetic; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051560:Proto-Oncogene Proteins c-bcl-6; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*; D000098546:Interleukin-21
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000098546:Interleukin-21