title: Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation.
abstract: Follicular T-helper (T(FH)) cells cooperate with GL7(+)CD95(+) germinal center (GC) B cells to induce antibody maturation. Herein, we identify the transcription factor IRF4 as a T-cell intrinsic precondition for T(FH) cell differentiation and GC formation. After immunization with protein or infection with the protozoon Leishmania major, draining lymph nodes (LNs) of IFN-regulatory factor-4 (Irf4(-/-)) mice lacked GCs and GC B cells despite developing normal initial hyperplasia. GCs were also absent in Peyer's patches of naive Irf4(-/-) mice. Accordingly, CD4(+) T cells within the LNs and Peyer's patches failed to express the T(FH) key transcription factor B-cell lymphoma-6 and other T(FH)-related molecules. During chronic leishmaniasis, the draining Irf4(-/-) LNs disappeared because of massive cell death. Adoptive transfer of WT CD4(+) T cells or few L. major primed WT T(FH) cells reconstituted GC formation, GC B-cell differentiation, and LN cell survival. In support of a T-cell intrinsic IRF4 activity, Irf4(-/-) T(FH) cell differentiation was not rescued by close neighborhood to transferred WT T(FH) cells. Together with its known B lineage-specific roles during plasma cell maturation and class switch, our study places IRF4 in the center of antibody production toward T-cell-dependent antigens.
authors.affiliation: Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Universität Marburg, 35043 Marburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bollig
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kellner
authors.forename: Waltraud
authors.initials: W
authors.lastname: Ackermann
authors.forename: Elfadil
authors.initials: E
authors.lastname: Abass
authors.forename: Hartmann
authors.initials: H
authors.lastname: Raifer
authors.forename: Bärbel
authors.initials: B
authors.lastname: Camara
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.forename: Gavin
authors.initials: G
authors.lastname: Giel
authors.forename: Evita
authors.initials: E
authors.lastname: Bothur
authors.forename: Magdalena
authors.initials: M
authors.lastname: Huber
authors.forename: Christoph
authors.initials: C
authors.lastname: Paul
authors.forename: Alexandra
authors.initials: A
authors.lastname: Elli
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kroczek
authors.forename: Roza
authors.initials: R
authors.lastname: Nurieva
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: Ralf
authors.initials: R
authors.lastname: Jacob
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Michael
authors.initials: M
authors.lastname: Lohoff
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology / Q000469:parasitology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D007378:Interleukins; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4