The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells

Xiao, Nengming; Eto, Danelle S.; Elly, Chris; Peng, Guiying; Crotty, Shane; Liu, Yun‐Cai

doi:10.1038/ni.2912

Cited by 105 publications

(129 citation statements)

References 49 publications

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“…Inducible T-cell costimulator (ICOS) signaling transiently inactivates forkhead box protein O1 (Foxo1), which, in turn, relieves Foxo1-dependent inhibition of Bcl6 expression and promotes TFH differentiation (12). Reduced Foxo1 abundance, either resulting from increased expression of ICOS induced by loss of Foxp1 or due to degradation by the E3 ubiquitin ligase ITCH, may enhance TFH-cell differentiation (13,14). Moreover, induced deficiency of the zinc finger transcription factor Krueppellike factor 2 (KLF2) in activated CD4…”

Section: Organs a Fraction Of Activated Cd4mentioning

confidence: 99%

miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

Serr

Fürst

Ott

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5)+CD4+ TFH precursor phenotype. During onset of islet autoimmunity, the frequency of TFH precursors was controlled by high expression of microRNA92a (miRNA92a). miRNA92a-mediated TFH precursor induction was regulated by phosphatase and tension homolog (PTEN) - phosphoinositol-3-kinase (PI3K) signaling involving PTEN and forkhead box protein O1 (Foxo1), supporting autoantibody generation and triggering the onset of islet autoimmunity. Moreover, we identify Krueppel-like factor 2 (KLF2) as a target of miRNA92a in regulating human TFH precursor induction. Importantly, a miRNA92a antagomir completely blocked induction of human TFH precursors in vitro. More importantly, in vivo application of a miRNA92a antagomir to nonobese diabetic (NOD) mice with ongoing islet autoimmunity resulted in a significant reduction of TFH precursors in peripheral blood and pancreatic lymph nodes. Moreover, miRNA92a antagomir application reduced immune infiltration and activation in pancreata of NOD mice as well as humanized NOD Scid IL2 receptor gamma chain knockout (NSG) human leucocyte antigen (HLA)-DQ8 transgenic animals. We therefore propose that miRNA92a and the PTEN-PI3K-KLF2 signaling network could function as targets for innovative precision medicines to reduce T1D islet autoimmunity.

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Section: Organs a Fraction Of Activated Cd4mentioning

confidence: 99%

miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

Serr

Fürst

Ott

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the study of Th cell development in mice genetically depleted of specific components of the TCR signaling cascade has underscored an intrinsic role of the TCR not only in initiating the activation program that will ultimately lead to CD4 + T cell differentiation but also in shaping the differentiation program itself. The strength of the TCR signal as well as of individual components of the TCR signaling cascade, including protein kinases (Fyn, Lck, Itk, protein kinase C-u, Akt1, Erk, p38), adaptors (LAT, SIT, raftlin, CARMA-1), and ubiquitin ligases (GRAIL, Itch), has been implicated in the differentiation and function of CD4 + T cells (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). We have recently identified Rai (also known as ShcC), a member of the Shc family of protein adaptors (21), as a negative regulator of Th17 cell development and expansion both in vitro and in vivo (22).…”

mentioning

confidence: 99%

The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis

Ulivieri

Savino

Luccarini

et al. 2016

The Journal of Immunology

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Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model. We found that, unexpectedly, EAE was less severe in Rai−/− mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai+/+ mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis.

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“…In the latter Foxo1 becomes dephosphorylated [40] or degraded [41,42]. More detailed analyses excluded a degradation of Foxo1 but demonstrated an accelerated Foxo1 dephosphorylation in SLy1 KO T cells after TCR stimulation, resulting in a faster reimport to the nucleus and induced expression of target genes, such as p27 and p130.…”

Section: Discussionmentioning

confidence: 98%

SLy1 regulates T‐cell proliferation during Listeria monocytogenes infection in a Foxo1‐dependent manner

et al. 2015

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Infection of mice with Listeria monocytogenes results in a strong T-cell response that is critical for an efficient defense. Here, we demonstrate that the adapter protein SLy1 (SH3-domain protein expressed in Lymphocytes 1) is essential for the generation of a fully functional T-cell response. The lack of SLy1 leads to reduced survival rates of infected mice. The increased susceptibility of SLy1 knock-out (KO) mice was caused by reduced proliferation of differentiated T cells. Ex vivo analyses of isolated SLy1 KO T cells displayed a dysregulation of Forkhead box protein O1 shuttling after TCR signaling, whichresulted in an increased expression of cell cycle inhibiting genes, and therefore, reduced expansion of the T-cell population. Forkhead box protein O1 shuttles to the cytoplasm after phosphorylation in a protein complex including 14-3-3 proteins. Interestingly, we observed a similar regulation for the adapter protein SLy1, where TCR stimulation results in SLy1 phosphorylation and SLy1 export to the cytoplasm. Moreover, immunoprecipitation analyses revealed a binding of SLy1 to 14-3-3 proteins. Altogether, this study describes SLy1 as an immunoregulatory protein, which is involved in the generation of adaptive immune responses during L. monocytogenes infection, and provides a model of how SLy1 regulates T-cell proliferation.Keywords: Foxo1 r Infection r Proliferation r SLy1 r T cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionInfection with the intracellular bacterium Listeria monocytogenes (LM) induces strong immune responses, which makes it ideally suited as a model to analyze the innate and adaptive immune responses in mice. Following infection, the innate immune system is quickly activated and serves as a first line defense to control Correspondence: Dr. Sandra Beer-Hammer e-mail: sandra.beer-hammer@uni-tuebingen.de the spreading of the bacteria. Neutrophils, macrophages, and NK cells have been shown to be part of this early response [1][2][3]. The importance of the innate immune system was further demonstrated by a significantly increased susceptibility of mice lacking , , , or IFNR-γ [7], and also by studies with SCID mice that develop chronic listeriosis, but are protected through the innate response from early death [8,9]. In contrast, the adaptive immune system requires several days to get fully activated and to generate Ag-specific T cells that resolve the infection and provide a long-lasting immunity [10].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 3088 Daniel Schäll et al. Eur. J. Immunol. 2015. 45: 3087-3097 SLy1 (SH3-domain protein expressed in Lymphocytes 1) is exclusively expressed in lymphocytes and is part of a family of adapter proteins comprising three members, SLy1 [11], SLy2 [12], and SASH1 (SAM-and SH3-domain containing protein 1) [13]. SLy1 and SLy2 are highly homologous, as both express a bipartite nuclear localization sequence as well as an SH3 and an SAM domain [11,14]. SL...

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The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells

Cited by 105 publications

References 49 publications

miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis

SLy1 regulates T‐cell proliferation during Listeria monocytogenes infection in a Foxo1‐dependent manner

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