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.

[5,6] and, most recently, Th9 cells producing 8]. All of these subsets differentiate from common precursor cells depending on * These authors contributed equally to this work.C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 3190 Hartmann Raifer et al. Eur. J. Immunol. 2012. 42: 3189-3201 the subset-driving cytokines during the first contact with the respective antigen. In this regard, IL-12 and IL-4 are considered to be the most important cytokines for generating Th1 or Th2 cells, respectively [9], while Th9 cells are raised in response to 8] and Th17 cells by 11]. Importantly, each of the Th subsets is also characterised by a lineagecharacterising transcription factor that is relevant for the generation and/or function of the respective subset. While T-bet and GATA3 characterise Th1 and Th2 cells, respectively [12,13], Th17 cells are dependent on RORγt and RORα [14,15], and Th9 cells require PU.1 and interferon regulatory factor 4 (IRF4) [16,17]. In contrast to conventional αβ T cells, γδ T cells form a TCR with γ and δ chains. These cells are part of the innate immune system, also produce cytokines such as IL-17 and IFN-γ and seem to produce these cytokines very rapidly [18]. Furthermore, unlike the relatively time-consuming processes that are necessary for Th-cell differentiation in the periphery as outlined above, γδ T cells are apparently pre-committed for cytokine production already in the thymus [19][20][21]. Within γδ T cells, IL-17 production correlates with a CCR6+ CD27 − phenotype [20,22,23] and the Vγ4 subset is particularly biased for IL-17 production [18]. Recently, a difference between αβ T cells and γδ T cells was also reported regarding the regulation of IL-17 production: the capacity to produce IL-17 directly ex vivo was strongly dependent on the NF-κB members RelA and RelB only in thymic γδ T cells but not in αβ T cells [24]. In contrast, thymic pre-commitment for IL-17-producing γδ T cells is suppressed by engagement of Skint-1, a thymic epithelial cell determinant [25]. With respect to function, IL-17-producing γδ T cells appear to form a major component of the defence against infections with bacteria such as Mycobacterium tuberculosis, Escherichia coli and pneumococci [26][27][28]. Likewise, IL-17-producing γδ T cells arise during autoimmune disorders such as rheumatoid arthritis or experimental autoimmune encephalomyelitis (EAE) [18,29,30]. We and others have studied the relevance of the interferon regulatory family of transcription factors for Th-cell differentiation. This family includes nine members (IRF1-9) in mammals that display gene homology and binding to relatively related motifs in the promoters of the genes they regulate [31]. Within interferon regulatory families, particularly IRF1, but to a lower degree also IRF2 and IRF8 are mandatory for Th1-cell differentiation [32]. In contrast, IRF4 has relatively pleiotropic roles by being absolutely required for Th2-and Th17-cell differentiation [33][34][35][36][37] and, as recently shown, for Th9-and T FH -cel...