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

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.