Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper type 2 cells. Here we show that IRF4 is also critical for the generation of interleukin 17-producing T helper cells (T(H)-17 cells), which are associated with experimental autoimmune encephalomyelitis. IRF4-deficient (Irf4(-/-)) mice did not develop experimental autoimmune encephalomyelitis, and T helper cells from such mice failed to differentiate into T(H)-17 cells. Transfer of wild-type T helper cells into Irf4(-/-) mice rendered the mice susceptible to experimental autoimmune encephalomyelitis. Irf4(-/-) T helper cells had less expression of RORgammat and more expression of Foxp3, transcription factors important for the differentiation of T(H)-17 and regulatory T cells, respectively. Altered regulation of both transcription factors contributed to the phenotype of Irf4(-/-) T helper cells. Our data position IRF4 at the center of T helper cell development, influencing not only T helper type 2 but also T(H)-17 differentiation.

Interleukin-6 (IL-6) is a pivotal cytokine with a diverse repertoire of physiological functions that include regulation of immune cell proliferation and differentiation. Dysregulation of IL-6 signalling is associated with inflammatory and lymphoproliferative disorders such as rheumatoid arthritis and Castleman disease, and several classes of therapeutics have been developed that target components of the IL-6 signalling pathway. So far, monoclonal antibodies against IL-6 or IL-6 receptor (IL-6R) and Janus kinases (JAK) inhibitors have been successfully developed for the treatment of autoimmune diseases such as rheumatoid arthritis. However, clinical trials of agents targeting IL-6 signalling have also raised questions about the diseases and patient populations for which such agents have an appropriate benefit-risk profile. Knowledge from clinical trials and advances in our understanding of the complexities of IL-6 signalling, including the potential to target an IL-6 trans-signalling pathway, are now indicating novel opportunities for therapeutic intervention. In this Review, we overview the roles of IL-6 in health and disease and analyse progress with several approaches of inhibiting IL-6-signalling, with the aim of illuminating when and how to apply IL-6 blockade.

Regulatory T (Treg) cells maintain immune homeostasis and prevent inflammatory and autoimmune responses. During development, thymocytes bearing a moderately self-reactive T cell receptor (TCR) can be selected to become Treg cells. Several observations suggest that also in the periphery mature Treg cells continuously receive self-reactive TCR signals. However, the importance of this inherent autoreactivity for Treg cell biology remains poorly defined. To address this open question, we genetically ablated the TCR of mature Treg cells in vivo. These experiments revealed that TCR-induced Treg lineage-defining Foxp3 expression and gene hypomethylation were uncoupled from TCR input in mature Treg cells. However, Treg cell homeostasis, cell-type-specific gene expression and suppressive function critically depend on continuous triggering of their TCR.

Summary Mice that lack interleukin-23 (IL-23) are resistant to T cell-mediated autoimmunity. Although IL-23 is a maturation factor for T helper 17 (Th17) cells, a subset of γδ T cells expresses the IL-23 receptor (IL-23R) constitutively. Using IL-23R reporter mice, we showed that γδ T cells were the first cells to respond to IL-23 during experimental autoimmune encephalomyelitis (EAE). Although γδ T cells produced Th17 cell-associated cytokines in response to IL-23, their major function was to prevent the development of regulatory T (Treg) cell responses. IL-23-activated γδ T cells rendered αβ effector T cells refractory to the suppressive activity of Treg cells and also prevented the conversion of conventional T cells into Foxp3+ Treg cells in vivo. Thus, IL-23, which by itself has no direct effect on Treg cells, is able to disarm Treg cell responses and promote antigen specific effector T cell responses via activating γδ T cells.

Peptide generation by the proteasome is rate-limiting in MHC class I-restricted antigen presentation in response to IFN-␥. IFN-␥-induced de novo formation of immunoproteasomes, therefore, essentially supports the rapid adjustment of the mammalian immune system. Here, we report that the molecular interplay between the proteasome maturation protein (POMP) and the proteasomal ␤5i subunit low molecular weight protein 7 (LMP7) has a key position in this immune adaptive program. IFN-␥-induced coincident biosynthesis of POMP and LMP7 and their direct interaction essentially accelerate immunoproteasome biogenesis compared with constitutive 20S proteasome assembly. The dynamics of this process is determined by rapid LMP7 activation and the immediate LMP7-dependent degradation of POMP. Silencing of POMP expression impairs recruitment of both ␤5 subunits into the proteasome complex, resulting in decreased proteasome activity, reduced MHC class I surface expression, and induction of apoptosis. Furthermore, our data reveal that immunoproteasomes exhibit a considerably shortened half-life, compared with constitutive proteasomes. In consequence, our studies demonstrate that the cytokine-induced rapid immune adaptation of the proteasome system is a tightly regulated and transient response allowing cells to return rapidly to a normal situation once immunoproteasome function is no longer required.antigen presentation ͉ immunoproteasome ͉ MHC class I

Th1 lymphocytes preferentially infiltrate into the spinal cord during EAE via a VLA-4–mediated mechanism while Th17 lymphocyte infiltration is dependent on LFA-1 expression.

The cellular sources of interleukin-6 (IL-6) that are relevant for the differentiation of TH17 cells remain unclear. Here, we used a novel strategy of IL-6 conditional deletion of distinct IL-6-producing cell types to show that Sirpα+ dendritic cells (DC) were essential for the generation of pathogenic TH17 cells. During the process of cognate interaction, Sirpα+ DCs trans-presented IL-6 to T cells using their own IL-6Rα. While ambient IL-6 was sufficient to suppress the induction of the transcription factor Foxp3 in T cells, IL-6 trans-presentation by DC-bound IL-6Rα (here defined as IL-6 cluster signaling) was required to prevent premature induction of IFN-γ in T cells and to generate pathogenic TH17 cells in vivo. These findings will guide therapeutic approaches for TH17-mediated autoimmune diseases.

Activation of naive CD8 + T cells with antigen in the absence of skewing cytokines triggers their differentiation into effector CTL, which induces death of target cells. We show that CD8 + T cells activated in the presence of the cytokines IL-6 or IL-21 plus TGF-b similar to CD4 + T cells, develop into IL-17-producing (Tc17) cells. These cells display greatly suppressed cytotoxic function along with low levels of the CTL markers: T-box transcription factor Eomesodermin, granzyme B and IFN-c. Instead, these cells express hallmark molecules of Th17 program including retinoic acid receptor-related orphan receptor (ROR)ct, RORa, IL-21 and IL-23R. The expression of the type 17 master regulator RORct is causally linked to Tc17 generation, because its overexpression stimulates production of IL-17 in the presence of IL-6 or IL-21. Both, upregulation of the type 17 program as well as suppression of CTL differentiation are STAT3 dependent. Furthermore, Tc17 cells producing IL-17 but not granzyme B are also detectable in EAE, a mouse model for multiple sclerosis. Our data point to the existence of mutually exclusive CTL and Tc17 developmental pathways in vitro and in vivo.Key words: CTL . EAE . RORgt . STAT3 . Tc17Supporting Information available online Introduction CTL are important effector cells in the immune response to intracellular pathogens and tumors. They differentiate from naive CD8 + T cells following activation by antigen in the absence of skewing cytokines, and during this process they acquire the ability to destroy their targets by releasing cytotoxic molecules such as perforin and granzymes, from granules into the immunological synapse. In addition, CTL secrete cytokines, mostly IFN-g and TNF-a, which function to induce or augment inflammation [1][2][3].Two T-box transcription factors, Eomesodermin (Eomes) and T-bet, are important for the development of effector and memory CTL [4][5][6]. Studies using deletion, overexpression or dominant negative analogs of these factors have suggested that both of them are involved in the regulation of expression of granzyme B and perforin [4,5,7]. Consistent with these data, CD8 + T cells with combined deletion of the Eomes and Tbx21 (encoding T-bet) genes differentiate into cells with highly impaired cytotoxic activity and IFN-g production [8]. Instead, these cells produce Th17 type cytokines and express the IL-23 receptor (IL-23R) as well as the transcription factor retinoic acid receptor-related orphan receptor (ROR)gt, both of 1716Frontline which are characteristic for the type 17 differentiation program [8]. Thus, the phenotype of CD8 + T cells deficient for both Eomes and T-bet is reminiscent of the newly described Th17-cell subset.Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22, which are highly pro-inflammatory and induce severe autoimmunity, e.g. during EAE, the mouse model for multiple sclerosis [9]. The differentiation of these cells requires TGF-b in combination with 11]. Two additional cytokines, IL-21 and IL-23, are also critically involved in the diffe...