Unlike αβ T cells, γδ T cells, LTi cells and NKT cells do not require IRF4 for the production of IL‐17A and IL‐22

Abstract

[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...

Effector γδ T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors

“…8B). Together with published findings on IRF4, also dispensable for IL-17 expression in gd27 2 cells (29,30), our data demonstrate that IL-17 production by gd27 2 cells, although dependent on the master transcription factor RORgt, does not rely on auxiliary transcriptional partners (BATF, RORa, IRF4) that promote CD4 Th17 cell differentiation.…”

“…Consistent with this, IRF4 has been recently shown to be dispensable for the differentiation of IL-17-producing gd T cells (29,30). Although IRF4 and BATF cooperate in conventional CD4 T cells, it has been shown that BATF has a direct impact on IL-17 expression by innate-like iNKT cells (31), whereas IRF4 was not required (29). Therefore, building on these foundations, and on our previous identification of effector gd T cell subsets segregated on the basis of CD27 expression (10,(32)(33)(34), we have in this work assessed the specific roles of the transcription factors T-bet, Eomes, RORgt, BATF, and RORa in the production of IFN-g and IL-17 by gd T cells in vitro and in vivo.…”

“…In fact, given their rather distinct differentiation dynamics, it is questionable whether the same principles apply to both T cell lineages. Consistent with this, IRF4 has been recently shown to be dispensable for the differentiation of IL-17-producing gd T cells (29,30). Although IRF4 and BATF cooperate in conventional CD4 T cells, it has been shown that BATF has a direct impact on IL-17 expression by innate-like iNKT cells (31), whereas IRF4 was not required (29).…”

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

“…However, the efficiency of the CD4-driven Cre recombinase in ILCs was challenged (45). Nevertheless, differential requirements for the transcription factor IRF4 were recently reported between Th17 cells and ILC3s for the production of both IL-22 and IL-17 (46). Moreover, previous work demonstrated that IL-17 production in ILC3s can occur in both a STAT3-dependent and STAT3-independent manner (34).…”

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

“…For example, the Notch-Hes1 pathway and the noncanonical (RelB) NF-kB pathway as well as, in a gd thymocyte-extrinsic manner, NIK and RelA expression in the thymus are required for the generation of gdT17 cells (6)(7)(8). In contrast, IRF4, which is critically required for Th17 cell differentiation, is dispensable for the development of gdT17 cells (9). Although probably irrelevant for the de novo generation of gdT17 cells in the thymus, STAT3 is required for the expansion of gdT17 cells, and the selective expansion of gdT17 cells by IL-7 was reported to depend on STAT3 (10).…”