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

摘要

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 hyper-plasia. 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 rt4~(-/-) 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.