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

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.