Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation

Nadine Bollig, Anne Brus̈tle, Kerstin Kellner, Waltraud Ackermann, Elfadil Abass, Hartmann Raifer, Bärbel Camara, Cornelia Brendel, Gavin Giel, Evita Bothur, Magdalena Huber, Christoph Paul, Alexandra Elli, Richard A. Kroczek, Roza Nurieva, Chen Dong, Ralf Jacob, Tak W. Mak*, Michael Lohoff

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

156 Citations (Scopus)

Abstract

Follicular T-helper (TFH) 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 TFH 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 TFH key transcription factor B-cell lymphoma- 6 and other TFH-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 TFH cells reconstituted GC formation, GC B-cell differentiation, and LN cell survival. In support of a T-cell intrinsic IRF4 activity, Irf4-/-TFH cell differentiation was not rescued by close neighborhood to transferred WT TFH 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.

Original languageEnglish
Pages (from-to)8664-8669
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number22
DOIs
Publication statusPublished - 29 May 2012
Externally publishedYes

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