Dendritic Cells Require STAT-1 Phosphorylated at Its Transactivating Domain for the Induction of Peptide-Specific CTL

Pilz, Andreas; Kratky, Wolfgang; Stockinger, Silvia; Simma, Olivia; Kalinke, Ulrich; Lingnau, Karen; Gabain, Alexander von; Stoiber, Dagmar; Sexl, Veronika; Kolbe, Thomas; Rülicke, Thomas; Müller, Mathias; Decker, Thomas

doi:10.4049/jimmunol.0901383

Cited by 34 publications

(33 citation statements)

References 56 publications

(46 reference statements)

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“…These findings are consistent with recent observations that type I IFNs can act directly on CD8 + T cells, facilitating clonal expansion and differentiation into effector and memory CD8 + T cells (16,31,41). Furthermore, other studies have shown that immunizations with synthetic CD8 + T cell peptide epitopes or with protein Ags (requiring cross-presentation) are strongly enhanced in the presence of type I IFN-inducing TLR ligands (42)(43)(44).…”

Section: Discussionsupporting

confidence: 81%

“…However, according to recent studies (16,31), it is more likely that signals downstream of the IFNAR contribute to increased survival and effector functions of CD8 + T cells. At this point, we cannot exclude a potential synergistic effect between direct type I IFN signaling on CD8 + T cells and additional signals provided by other cell types, as it has been reported that the immunostimulatory activity of type I IFN stems, at least in part, from its ability to induce DC maturation (44,49).…”

Section: Discussionmentioning

confidence: 99%

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Type I IFN Substitutes for T Cell Help during Viral Infections

Wiesel

Kratky

Oxenius

2011

The Journal of Immunology

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Certain virus infections depend on the presence of T cell help for the generation of primary CD8+ T cell responses. However, the mechanisms that render these particular viral infections T cell help dependent is largely unknown. In this study, we compared CD8+ T cell responses elicited by lymphocytic choriomeningitis virus infection, as prototype of a T cell help independent infection, with T cell help dependent CD8+ T cell responses induced by vaccinia virus infection. In this paper, we show that a key parameter decisive for T cell help independence is the ability of an infectious agent to stimulate early and robust production of type I IFN. Experimental provision of type I IFN during VV infection rendered the ensuing CD8+ T cell response completely T cell help independent. Our results support a model in which type I IFN has to be present during the first 3 d of Ag encounter and has to act directly on the responding CD8+ T cells to promote their survival and effector differentiation. We show that type I IFN signaling on responding CD8+ T cells induces profound upregulation of CD25 and increased IL-2 expression; however, neither this nor IL-15 accounts for the type I IFN effects on responding CD8+ T cells. Thus, type I IFN can effectively replace the requirement of T cell help by directly promoting CD8+ T cell survival and differentiation independent of the type I IFN-induced cytokines IL-2 and IL-15.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Type I IFN Substitutes for T Cell Help during Viral Infections

Wiesel

Kratky

Oxenius

2011

The Journal of Immunology

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“…The mechanistic basis for this immunodeficiency involves impaired memory development, CTL generation, and DC function (63)(64)(65). Our results now provide evidence that Stat1 is an inhibitor of Tregs and that in the absence of Stat1, enhanced expansion of Tregs may lead to blunting of the Th1 response, thereby contributing to immunosuppression.…”

Section: Discussionmentioning

confidence: 49%

Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice

Ma¹,

Lu²,

Ziegler³

et al. 2011

J. Clin. Invest.

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“…The latter has been shown to be important for maximal transcriptional activity of Stat1/3/4 but not of Stat5a and Stat5b. 22 Biochemical and biologic functions of Stat serine phosphorylation also include DNA binding, 23,37 cofactor association, 38 immune responses, 39,40 and transformation. 41,42 Interestingly, we found the C-terminally mapped serines of Stat5a (Ser725/779) to be highly phosphorylated in human bcr/abl ϩ CML samples, human lymphoma cell lines, primary leukemia patient samples, and Ba/F3 cells overexpressing different fusion tyrosine kinases.…”

Section: Discussionmentioning

confidence: 99%

Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation

Friedbichler

Kerényi

Kovacic

et al. 2010

Blood

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IntroductionHematopoietic development is regulated by cytokine-or growth factor-activated signaling pathways, among which the Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway plays a major role. [1][2][3] Four Jak kinases and 7 Stat proteins regulate a wide spectrum of cellular functions such as proliferation, survival, and differentiation. 4 Stats are latent transcription factors that constantly shuttle between the nucleus and the cytoplasm. Their activity is tightly regulated by protein tyrosine kinases. Phosphorylation of a positionally conserved tyrosine residue triggers dimerization, efficient nuclear translocation, and subsequent binding of Stats to specific promoter sequences. 5 Target genes regulated by Stat5 proteins and their cofactors are essential for hematopoietic stem cell maintenance, lineage commitment, self-renewal, and survival of committed hematopoietic progenitors as well as for mature cells of both myeloerythroid and lymphoid lineage. [6][7][8] Although there is considerable functional overlap, Stat5a and Stat5b proteins also have distinct functions due to isoformspecific differences in mRNA levels, 3,5 nucleocytoplasmic shuttling, 9,10 and activation by tyrosine and/or serine phosphorylation. 11 Hyperactivated Stat5a and Stat5b proteins have been implicated in several hematopoietic malignancies and many solid tumors. [1][2][3] Yet to date, there are no reports of activating mutations in Stat5 proteins. Persistent tyrosine phosphorylation of Stat5 was found to be caused by deregulated cytokine signaling 12 or perturbation of upstream molecules, which mostly results from receptor mutations or chromosomal rearrangement. Well-known examples of this are the point mutation Jak2-V617F 13,14 and chromosomal translocations such as Bcr-Abl. 15,16 Furthermore, it has been shown that the presence of Stat5 proteins is required for Bcr-Abl-induced transformation and development of leukemia. 17 This is why Stat5 proteins and their activation status are thought to have a key role in leukemogenesis. Moreover, the transforming capacity of oncogenic Stat5 is not limited to its role as a transcription factor in the nucleus. Recent studies have demonstrated that oncogenic Stat5a also has a cytoplasmic role that links Jak/Stat signaling to the activation of the PI3K-Akt-mTOR signaling pathway via Gab2 [18][19][20] and that Stat5 acts as a repressor of Bcl-2 member-regulating microRNAs (miRNAs) 15/16. 21 In addition to tyrosine phosphorylation, the activity of several Stat proteins was shown to be modulated by serine phosphorylation (reviewed in Decker and Kovarik 22 ). In the highly homologous Stat5a and Stat5b proteins, distinct serine residues in the carboxyterminal transactivation domain, the least conserved region of Stat proteins, 2,3 were found to be phosphorylated. These serine moieties, however, are located in perfectly conserved Pro-Ser-Pro (PSP) motifs at positions 725 (Stat5a) and 730 (Stat5b 11,[23][24][25][26][27] Using a mouse transplantation model, 28,29 the pr...

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Dendritic Cells Require STAT-1 Phosphorylated at Its Transactivating Domain for the Induction of Peptide-Specific CTL

Cited by 34 publications

References 56 publications

Type I IFN Substitutes for T Cell Help during Viral Infections

Type I IFN Substitutes for T Cell Help during Viral Infections

Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice

Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation

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