In vivo regulation of Bcl6 and T follicular helper cell development.
Follicular helper T (T(FH)) cells, defined by expression of the surface markers CXCR5 and programmed death receptor-1 (PD-1) and synthesis of IL-21, require upregulation of the transcriptional repressor Bcl6 for their development and function in B cell maturation in germinal centers. We have explored the role of B cells and the cytokines IL-6 and IL-21 in the in vivo regulation of Bcl6 expression and T(FH) cell development. We found that T(FH) cells are characterized by a Bcl6-dependent downregulation of P-selectin glycoprotein ligand 1 (PSGL1, a CCL19- and CCL21-binding protein), indicating that, like CXCR5 and PD-1 upregulation, modulation of PSGL1 expression is part of the T(FH) cell program of differentiation. B cells were neither required for initial upregulation of Bcl6 nor PSGL1 downregulation, suggesting these events preceded T-B cell interactions, although they were required for full development of the T(FH) cell phenotype, including CXCR5 and PD-1 upregulation, and IL-21 synthesis. Bcl6 upregulation and T(FH) cell differentiation were independent of IL-6 and IL-21, revealing that either cytokine is not absolutely required for development of Bcl6(+) T(FH) cells in vivo. These data increase our understanding of Bcl6 regulation in T(FH) cells and their differentiation in vivo and identifies a new surface marker that may be functionally relevant in this subset.
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
Amanda C
AC
Poholek
Kyle
K
Hansen
Sairy G
SG
Hernandez
Danelle
D
Eto
Anmol
A
Chandele
Jason S
JS
Weinstein
Xuemei
X
Dong
Jared M
JM
Odegard
Susan M
SM
Kaech
Alexander L
AL
Dent
Shane
S
Crotty
Joe
J
Craft
D000818:Animals; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D016130:Immunophenotyping; D008211:Lymphocyte Cooperation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051560:Proto-Oncogene Proteins c-bcl-6; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D051560:Proto-Oncogene Proteins c-bcl-6