Abstract
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.