Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 22, Pages 8664-8669Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1205834109
Keywords
interleukin-21; inducible costimulator; CXC-chemokine receptor 5; apoptosis
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Funding
- Landes-Offensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz (LOEWE) (Germany)
- Behring-Rontgen-Stiftung
- Deutsche Forschungsgemeinschaft [SFB TR22]
- Deutscher Akademischer Austauschdienst, Germany
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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.
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