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Rahul Roychoudhuri,
Kiyoshi Hirahara,
Kambiz Mousavi,
David Clever,
Christopher A Klebanoff,
Michael Bonelli,
Giuseppe Sciumè,
Hossein Zare,
Golnaz Vahedi,
Barbara Dema, [......],
Juan Rivera,
Francesco M Marincola,
Atsushi Nakamura,
Vittorio Sartorelli,
Yuka Kanno,
Luca Gattinoni,
Akihiko Muto,
Kazuhiko Igarashi, John J O'Shea,
Nicholas P Restifo
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ABSTRACT: Through their functional diversification, distinct lineages of CD4(+) T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4(+) T cells. BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within TH1, TH2 and TH17 cell lineages. These findings identify BACH2 as a key regulator of CD4(+) T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.
Nature 06/2013; · 36.28 Impact Factor
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ABSTRACT: CD4 helper T cells are critical for proper immune cell homeostasis and host defense but are also major contributors to immune and inflammatory disease. Arising from a simple biphasic model of differentiation (ie, TH1 and TH2 cells). A bewildering number of fates seem possible for helper T cells. To what extent different helper cell subsets maintain their characteristic gene expression profiles or exhibit functional plasticity is a hotly debated topic. In this review we will discuss how the expression of "signature cytokines" and "master regulator" transcription factors do not neatly conform to a simple helper T-cell paradigm. Although this might seem confusing, the good news is that the newly recognized complexity fits better with our understanding of immunopathogenesis. Finally, we will discuss factors, including epigenetic regulation and metabolic alterations, that contribute to helper cell specificity and plasticity.
The Journal of allergy and clinical immunology 05/2013; 131(5):1276-87. · 9.17 Impact Factor
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ABSTRACT: Naïve T cells differentiate and become distinct subsets in response to changes in the cytokine milieu. Such specialization arises due to a complex and dynamic utilization of cis-regulatory enhancer elements. In this brief essay, we review recent findings on the relative contributions of sensors of the cytokine milieu, especially the STAT family transcription factors, 'master regulators', and other transcription factors in the enhancer architecture of T cells. These findings provide new insights into how signal transduction impinges upon the genome. This article is protected by copyright. All rights reserved.
Immunology 04/2013; · 3.32 Impact Factor
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ABSTRACT: CD4(+) T cells are critical for the elimination of an immense array of microbial pathogens. Among the ways they accomplish this task is to generate progeny with specialized, characteristic patterns of gene expression. From this perspective, helper cells can be viewed as pluripotent precursors that adopt distinct cell fates. Although there are aspects of helper cell differentiation that can be modeled as a classic cell fate commitment, CD4(+) T cells also maintain considerable flexibility in their transcriptional program. This makes sense in terms of host defense, but raises the question of how these remarkable cells balance both these requirements, a high degree of specific gene expression and the capacity for plasticity. In this review, we discuss recent advances in our understanding of CD4(+) T-cell specification, focusing on how genomic perspectives have influenced our views of these processes. The relative contributions of sensors of the cytokine milieu, especially the signal transducer and activator of transcription family transcription factors, 'master regulators', and other transcription factors are considered as they relate to the helper cell transcriptome and epigenome.
Immunological Reviews 03/2013; 252(1):24-40. · 11.15 Impact Factor
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ABSTRACT: The molecular biology revolution coupled with the development of monoclonal antibody technology enabled remarkable progress in rheumatology therapy, comprising an array of highly effective biologic agents. With advances in understanding of the molecular nature of immune cell receptors came elucidation of intracellular signalling pathways downstream of these receptors. These discoveries raise the question of whether selective targeting of key intracellular factors with small molecules would add to the rheumatologic armamentarium. In this Review, we discuss several examples of this therapeutic strategy that seem to be successful, and consider their implications for the future of immune-targeted treatments. We focus on kinase inhibitors, primarily those targeting Janus kinase family members and spleen tyrosine kinase, given their advanced status in clinical development and application. We also summarize other targets involved in signalling pathways that might offer promise for therapeutic intervention in the future.
Nature Reviews Rheumatology 02/2013; 9(3):173-82. · 8.39 Impact Factor
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ABSTRACT: CD4(+) T helper (Th) cells differentiate into distinct effector subsets that are critical for host defense, but are also implicated in the pathogenesis of autoimmune disorders. Thelper17 (Th17) cells in particular are emerging as important drivers of multiple diseases including psoriasis, spondyloarthropathy and multiple sclerosis. To gain insight into the function of Th17 cells, we performed transcriptional profiling in hopes of elucidating products not previously recognized as being functionally relevant in these T cells. Herein, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted protein with pleiotropic effects on cellular growth, survival and integrity of the extracellular matrix, is preferentially produced by Th17 and Th1 cells. We further show that Th1 and Th17 cell TIMP1 regulation follows separate mechanisms with a requirement for STAT4 in the former and STAT3 in the latter. Finally, we demonstrate that when restricted to T cells, expression of TIMP1 promotes neuropathology in experimental allergic encephalomyelitis.
PLoS ONE 01/2013; 8(3):e59367. · 4.09 Impact Factor
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Giuseppe Sciumé,
Kiyoshi Hirahara,
Hayato Takahashi,
Arian Laurence,
Alejandro V Villarino,
Kentner L Singleton,
Sean P Spencer,
Christoph Wilhelm,
Amanda C Poholek,
Golnaz Vahedi,
Yuka Kanno,
Yasmine Belkaid, John J O'Shea
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ABSTRACT: Interleukin (IL)-22-producing innate lymphoid cells (ILCs; ILC22) comprise a heterogeneous population of cells that are dependent on the transcription factor retinoid-related orphan γt (RORγt) and are critical for barrier function of the intestinal mucosa. A distinct ILC22 subset expresses the natural cytotoxicity receptor NKp46 (NKp46(+) ILC22); however, the factors that contribute to the generation of this population versus other subsets are largely unknown. Herein, we show that T-bet (encoded by Tbx21) was highly expressed in NKp46(+) ILC22, a feature shared by all NKp46(+) cells present in the intestine but not by other IL-22-producing populations. Accordingly, the absence of T-bet resulted in loss of NKp46(+) ILC22 in the intestinal lamina propria. The residual NKp46(+) ILC22 present in Tbx21(-/-) mice showed a marked reduction of Rorγt expression and impairment in IL-22 production. Generation and functions of gut NK1.1(+) cells were also altered. Bone marrow chimera experiments revealed a cell-intrinsic requirement for T-bet in these subsets and competitive reconstitution experiments revealed roles for T-bet in multiple ILC subsets. Thus, T-bet has a general importance for ILC in the gut and plays a selective and critical role in the generation of NKp46(+) ILC22.
Journal of Experimental Medicine 12/2012; · 13.85 Impact Factor
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ABSTRACT: Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. Although enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4(+) T cells as a model of differentiation, mapping the activity of cell-type-specific enhancer elements in T helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the activation of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells.
Cell 11/2012; 151(5):981-93. · 32.40 Impact Factor
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Andrea C Carpenter,
John R Grainger,
Yumei Xiong,
Yuka Kanno,
H Hamlet Chu,
Lie Wang,
Shruti Naik,
Liliane Dos Santos,
Lai Wei,
Marc K Jenkins, John J O'Shea,
Yasmine Belkaid,
Rémy Bosselut
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ABSTRACT: T helper (Th) cells are critical for defenses against infection and recognize peptides bound to class II major histocompatibility complex (MHC II) molecules. Although transcription factors have been identified that direct Th cells into specific effector fates, whether a "master" regulator controls the developmental program common to all Th cells remains unclear. Here, we showed that the two transcription factors Thpok and LRF share this function. Although disruption of both factors did not prevent the generation of MHC II-specific T cells, these cells failed to express Th cell genes or undergo Th cell differentiation in vivo. In contrast, T cells lacking Thpok, which only displayed LRF-dependent functions, contributed to multiple effector responses, both in vitro and in vivo, with the notable exception of Th2 cell responses that control extracellular parasites. These findings identify the Thpok-LRF pair as a core node of Th cell differentiation and function.
Immunity 10/2012; 37(4):622-33. · 21.64 Impact Factor
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ABSTRACT: IL-15 is an important IL-2-related cytokine whose role in Th17 cell biology has not been fully elucidated. In this study, we show that exogenous IL-15 decreased IL-17A production in Th17 cultures. Neutralization of IL-15 using an Ab led to increases in IL-17A production in Th17 cultures. Both Il15(-/-) and Il15r(-/-) T cell cultures displayed higher frequency of IL-17A producers and higher amounts of IL-17A in the supernatants compared with those of wild-type (WT) cells in vitro. IL-15 down-modulated IL-17A production independently of retinoic acid-related orphan receptor-γt, Foxp3, and IFN-γ expression. Both Th17 cells and APCs produced IL-15, which induced binding of STAT5, an apparent repressor to the Il17 locus in CD4 T cells. Also, in a model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), Il15(-/-) mice displayed exacerbated inflammation-correlating with increased IL-17A production by their CD4(+) T cells-compared with WT controls. Exogenous IL-15 administration and IL-17A neutralization reduced the severity of EAE in Il15(-/-) mice. Taken together, these data indicate that IL-15 has a negative regulatory role in fine-tuning of IL-17A production and Th17-mediated inflammation.
The Journal of Immunology 09/2012; 189(9):4237-46. · 5.79 Impact Factor
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ABSTRACT: Type 1 IFNs can conditionally activate all of the signal transducers and activators of transcription molecules (STATs), including STAT4. The best-characterized signaling pathways use STAT1, however, and type 1 IFN inhibition of cell proliferation is STAT1 dependent. We report that type 1 IFNs can basally stimulate STAT1- and STAT4-dependent effects in CD8 T cells, but that CD8 T cells responding to infections of mice with lymphocytic choriomenigitis virus have elevated STAT4 and lower STAT1 expression with significant consequences for modifying the effects of type 1 IFN exposure. The phenotype was associated with preferential type 1 IFN activation of STAT4 as compared to STAT1. Stimulation through the TCR induced elevated STAT4 expression, and STAT4 was required for peak expansion of antigen-specific CD8 T cells, low STAT1 levels, and resistance to type 1 IFN-mediated inhibition of proliferation. Thus, a mechanism is discovered for regulating the consequences of type 1 IFN exposure in CD8 T cells, with STAT4 acting as a key molecule in driving optimal antigen-specific responses and overcoming STAT1-dependent inhibition of proliferation.
Blood 09/2012; · 9.90 Impact Factor
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ABSTRACT: Cytokines are critical for normal cell growth and immunoregulation but also contribute to growth of malignant cells and drive immune-mediated disease. A large subset of immunoregulatory cytokines uses the type I and type II cytokine receptors and pharmacological targeting of these cytokines/cytokines receptors has proven to be efficacious in treating immune and inflammatory diseases. These receptors rely on Janus family of kinases (Jaks) for signal transduction. Recently the first Jak inhibitor (jakinib) has been approved by the FDA and a second has been recommended for approval. Many other Jakinibs are likely to follow and in this brief review, we will discuss the state-of-the art of this new class of pharmacological agents.
Current Opinion in Pharmacology 07/2012; 12(4):464-70. · 6.86 Impact Factor
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Kiyoshi Hirahara,
Kamran Ghoreschi,
Xiang-Ping Yang,
Hayato Takahashi,
Arian Laurence,
Golnaz Vahedi,
Giuseppe Sciumè,
Aisling O'Hara Hall,
Christopher D Dupont,
Loise M Francisco,
Qian Chen,
Masao Tanaka,
Yuka Kanno,
Hong-Wei Sun,
Arlene H Sharpe,
Christopher A Hunter, John J O'Shea
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ABSTRACT: Interleukin-27 (IL-27) is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naive T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription 1 (STAT1)-dependent manner. When cocultured with naive CD4(+) T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, coadministration of naive TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4(+) T cells can restrict differentiation of Th17 cells in trans.
Immunity 06/2012; 36(6):1017-30. · 21.64 Impact Factor
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Hayato Takahashi,
Tomohiko Kanno,
Shingo Nakayamada,
Kiyoshi Hirahara,
Giuseppe Sciumè,
Stefan A Muljo,
Stefan Kuchen,
Rafael Casellas,
Lai Wei,
Yuka Kanno, John J O'Shea
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ABSTRACT: Distinct CD4(+) T cell subsets are critical for host defense and immunoregulation. Although these subsets can act as terminally differentiated lineages, they have been increasingly noted to demonstrated plasticity. MicroRNAs are factors that control T cell stability and plasticity. Here we report that naturally occurring regulatory T cells (T(reg) cells) had high expression of the microRNA miR-10a and that miR-10a was induced by retinoic acid and transforming growth factor-β (TGF-β) in inducible T(reg) cells. By simultaneously targeting the transcriptional repressor Bcl-6 and the corepressor Ncor2, miR-10a attenuated the phenotypic conversion of inducible T(reg) cells into follicular helper T cells. We also found that miR-10a limited differentiation into the T(H)17 subset of helper T cells and therefore represents a factor that can fine-tune the plasticity and fate of helper T cells.
Nature Immunology 04/2012; 13(6):587-95. · 26.01 Impact Factor
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ABSTRACT: CD4(+) helper T cells play crucial roles for host defense and immune-mediated disease by their ability to differentiate into specialized subsets. These subsets attain restricted patterns of cytokine secretion and specific expression of master transcription factors in response to microbial pathogens. Classically, the various helper CD4(+) T cell subsets have been viewed as terminally differentiated lineages with limited flexibility. However, following the recognition of new subsets, there is increased recognition of plasticity. In this review, we highlight recent advances that pertain to this topic and the mechanisms that contribute to helper CD4(+) T cell differentiation and plasticity.
Current opinion in immunology 02/2012; 24(3):297-302. · 10.88 Impact Factor
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ABSTRACT: Protein kinases are fundamental components of diverse signaling pathways, including immune cells. Their essential functions have made them effective therapeutic targets. Initially, the expectation was that a high degree of selectivity would be critical; however, with time, the use of "multikinase" inhibitors has expanded. Moreover, the spectrum of diseases in which kinase inhibitors are used has also expanded to include not only malignancies but also immune-mediated diseases. At present, thirteen kinase inhibitors have been approved in the United States, all for oncologic indications. However, there are a growing number of molecules, including several Janus kinase inhibitors, that are being tested in clinical trials for autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel diseases. It appears likely that this new class of immunomodulatory drugs will have a major impact on the treatment of immune-mediated diseases in the near future.
F1000 Medicine Reports 01/2012; 4:5.
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Shingo Nakayamada,
Yuka Kanno,
Hayato Takahashi,
Dragana Jankovic,
Kristina T Lu,
Thomas A Johnson,
Hong-wei Sun,
Golnaz Vahedi,
Ofir Hakim,
Robin Handon,
Pamela L Schwartzberg,
Gordon L Hager, John J O'Shea
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ABSTRACT: Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we showed interleukin-12 acting via the transcription factor STAT4 induced both Il21 and Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced the transcription factor T-bet. With ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh cell-like phenotype in the late phase of Th1 cell specification. Tfh-like cells were rapidly generated after Toxoplasma gondii infection in mice, but T-bet constrained Tfh cell expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 cells share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh cell functionalities, promoting full Th1 cell differentiation.
Immunity 12/2011; 35(6):919-31. · 21.64 Impact Factor
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The Journal of Immunology 12/2011; 187(11):5475-8. · 5.79 Impact Factor
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ABSTRACT: CD4(+) T cells have critical roles in orchestrating immune responses to diverse microbial pathogens. This is accomplished through the differentiation of CD4(+) T helper cells to specialized subsets in response to microbial pathogens, which evoke a distinct cytokine milieu. Signal transducer and activator of transcription family transcription factors sense these cytokines and they in turn regulate expression of lineage-defining master regulators that programme selective gene expression, resulting in distinctive phenotypes. However, phenotype and restricted gene expression are determined not only by the action of transcription factors; chromatin accessibility is required for these factors to exert their effect. Technical advances have greatly expanded our understanding of transcription factor action and dynamic changes in the epigenome that accompany cellular differentiation. In this review, we will discuss recent progress in the understanding of how cytokines influence gene expression and epigenetic modifications, and the impact of these findings on our views of helper cell lineage commitment and plasticity.
Immunology 11/2011; 134(3):235-45. · 3.32 Impact Factor
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Kristina T Lu,
Yuka Kanno,
Jennifer L Cannons,
Robin Handon,
Paul Bible,
Abdel G Elkahloun,
Stacie M Anderson,
Lai Wei,
Hongwei Sun, John J O'Shea,
Pamela L Schwartzberg
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ABSTRACT: Follicular T helper (Tfh) cells provide critical help to B cells for germinal center (GC) formation. Mutations affecting SLAM-associated protein (SAP) prevent GC formation because of defective T cell-B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent "Tfh-like" cells that expressed interleukin-21, Tfh cell markers, and Bcl6 and rescued GC formation in SAP-deficient hosts better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wild-type, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, Th1, Th2, and Th17 cells could be reprogrammed to obtain Tfh cell characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3, and Rorc in Tfh-like and ex vivo Tfh cells and on Bcl6 in non-Tfh cells, supporting the concept of plasticity between Tfh and other Th cell populations.
Immunity 10/2011; 35(4):622-32. · 21.64 Impact Factor
