Precise control of the timing and magnitude of Notch signaling is essential for the normal development of many tissues, but the feedback loops that regulate Notch are poorly understood. Developing T ...cells provide an excellent context to address this issue. Notch1 signals initiate T-cell development and increase in intensity during maturation of early T-cell progenitors (ETP) to the DN3 stage. As DN3 cells undergo beta-selection, during which cells expressing functionally rearranged TCRbeta proliferate and differentiate into CD4(+)CD8(+) progeny, Notch1 signaling is abruptly down-regulated. In this report, we investigate the mechanisms that control Notch1 expression during thymopoiesis. We show that Notch1 and E2A directly regulate Notch1 transcription in pre-beta-selected thymocytes. Following successful beta-selection, pre-TCR signaling rapidly inhibits Notch1 transcription via signals that up-regulate Id3, an E2A inhibitor. Consistent with a regulatory role for Id3 in Notch1 down-regulation, post-beta-selected Id3-deficient thymocytes maintain Notch1 transcription, whereas enforced Id3 expression decreases Notch1 expression and abrogates Notch1-dependent T-cell survival. These data provide new insights into Notch1 regulation in T-cell progenitors and reveal a direct link between pre-TCR signaling and Notch1 expression during thymocyte development. Our findings also suggest new strategies for inhibiting Notch1 signaling in pathologic conditions.
The human FOXP3 molecule is an oligomeric transcriptional factor able to mediate activities that characterize T regulatory cells, a class of lymphocytes central to the regulation of immune responses. ...The activity of FOXP3 is regulated at the posttranslational level, in part by two histone acetyltransferases (HATs): TIP60 and p300. TIP60 and p300 work cooperatively to regulate FOXP3 activity. Initially, p300 and TIP60 interactions lead to the activation of TIP60 and facilitate acetylation of K327 of TIP60, which functions as a molecular switch to allow TIP60 to change binding partners. Subsequently, p300 is released from this complex, and TIP60 interacts with and acetylates FOXP3. Maximal induction of FOXP3 activities is observed when both p300 and TIP60 are able to undergo cooperative interactions. Conditional knockout of TIP60 in Treg cells significantly decreases the Treg population in the peripheral immune organs, leading to a scurfy-like fatal autoimmune disease.
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•p300 and TIP60 work cooperatively to promote FOXP3 acetylation•TIP60 K327 acetylation allows TIP60 to switch binding partners•p300 conditional knockout in Treg cells leads to minimal changes in Treg functions•TIP60 conditional knockout in Treg cells results in fatal autoimmune disease
Greene and colleagues now reveal a cooperative effect between TIP60 and p300 in promoting Foxp3 acetylation, important for regulation of Treg function. TIP60 lysine 327 functions as a molecular switch to regulate the interaction of TIP60 and its binding partners, and K327 acetylation dissociates TIP60 from p300 and promotes binding of TIP60 to its downstream substrates. In addition, the authors show that TIP60 plays a critical role in regulating the peripheral homeostasis of Treg cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Notch signaling plays multiple roles in T cell development. Following thymic entry, Notch signals are required to specify the T cell fate from a multipotent hematopoietic progenitor. At ...subsequent steps in early T cell development, Notch provides important differentiation, survival, proliferation and metabolic signals. This review focuses on the multiple functions of Notch in early T cell development, from T cell specification in the thymus through beta selection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Trib2 is highly expressed in human T cell acute lymphoblastic leukemia (T-ALL) and is a direct transcriptional target of the oncogenic drivers Notch and TAL1. In human TAL1-driven T-ALL cell lines, ...Trib2 is proposed to function as an important survival factor, but there is limited information about the role of Trib2 in primary T-ALL. In this study, we investigated the role of Trib2 in the initiation and maintenance of Notch-dependent T-ALL. Trib2 had no effect on the growth and survival of murine T-ALL cell lines in vitro when expression was blocked by shRNAs. To test the function of Trib2 on leukemogenesis in vivo, we generated Trib2 knockout mice. Mice were born at the expected Mendelian frequencies without gross developmental anomalies. Adult mice did not develop pathology or shortened survival, and hematopoiesis, including T cell development, was unperturbed. Using a retroviral model of Notch-induced T-ALL, deletion of Trib2 unexpectedly decreased the latency and increased the penetrance of T-ALL development in vivo. Immunoblotting of primary murine T-ALL cells showed that the absence of Trib2 increased C/EBPα expression, a known regulator of cell proliferation, and did not alter AKT or ERK phosphorylation. Although Trib2 was suggested to be highly expressed in T-ALL, transcriptomic analysis of two independent T-ALL cohorts showed that low Trib2 expression correlated with the TLX1-expressing cortical mature T-ALL subtype, whereas high Trib2 expression correlated with the LYL1-expressing early immature T-ALL subtype. These data indicate that Trib2 has a complex role in the pathogenesis of Notch-driven T-ALL, which may vary between different T-ALL subtypes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
A physical mechanism that drives FU Orionis-type outbursts is reconsidered. We study the effect of the inner part of a circumstellar disk covering a region from near the central star to a ...radius of approximately 5 au (hereafter, the inner disk). Using the fluctuating mass accretion rate onto the inner disk $\dot{M}\,_{\rm out}$, we consider the viscous evolution of the inner disk and the time variability of the mass accretion rate onto the central star $\dot{M}\,_{\rm in}$ by means of numerical calculation of an unsteady viscous accretion disk in a one-dimensional axisymmetric model. First, we calculate the evolution of the inner disk assuming an oscillating $\dot{M}\,_{\rm out}$. It is shown that the time variability of $\dot{M}\,_{\rm in}$ does not coincide with $\dot{M}\,_{\rm out}$ due to viscous diffusion. Second, we investigate the properties of spontaneous outbursts with temporally constant $\dot{M}\,_{\rm out}$. Outbursts occur only in a limited range of mass accretion rates onto the inner disk of $10^{-10}<\dot{M}\,_{\rm out}< 3\times 10^{-6}{\,M}_{\odot }\:$yr−1 due to the gravo-magneto limit cycle (GML). Finally, we discuss the case with a combination of episodic $\dot{M}\,_{\rm out}$ and accretion outbursts caused by the GML in the inner disk. The GML can drive accretion outbursts onto the star even for the case of fluctuating $\dot{M}\,_{\rm out}$, although fluctuations of $\dot{M}\,$ decay while transmitting the inner disk inwards. We have newly identified two modes of outburst, one spontaneous and one stimulated. In the stimulated mode of outburst, $\dot{M}\,_{\rm out}$ does appear directly in $\dot{M}\,_{\rm in}$ (the latter defining the stellar accretion luminosity). In the spontaneous mode of outburst, $\dot{M}\,_{\rm out}$ appears as the interval between outbursts.
Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 ...transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner.
We generated a mouse line in which the src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130(F759/F759)). The ...gp130(F759/F759) mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130(F759/F759) T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.
BackgroundAlthough immune checkpoint blockade revolutionized cancer therapy, response rates have been mixed in gynecological malignancies. While uterine endometrial cancer with high microsatellite ...instability (MSIHI) and high tumor mutational burden (TMB) respond robustly to checkpoint blockade, high-grade serous ovarian cancer (HGSOC) with low TMB respond modestly. Currently, there has been no known immune signature or T cell phenotype that predicts clinical response in gynecological tumors.MethodsTo dissect the immune landscape and T cell phenotypes in gynecological cancer patients receiving PD-1 blockade, we used high-dimensional cytometry (flow cytometry and mass cytometry (CyTOF)). We performed longitudinal deep immune profiling of PBMC from patients with recurrent uterine endometrial cancer receiving single-arm nivolumab, and HSGOC patients receiving neoadjuvant nivolumab plus platinum-based chemotherapy prior to debulking surgery.ResultsChemotherapy-resistant MSI-H uterine cancer patients treated with nivolumab had a proliferative T cell response 2–4 weeks post PD-1 blockade, consistent with responses seen in high TMB melanoma and lung cancer. The responding Ki67+ CD8 T cell population was largely CD45RAloCD27hi or CD45RAloCD27lo and highly expressed PD1, CTLA-4, and CD39, consistent with the phenotype of exhausted T cells (TEX). These exhausted-like cells are enriched in responders, whereas early expansion Tregs are enriched in non-responders. Unlike patients with uterine endometrial cancer, patients with TMBlo ovarian cancer did not have a clear proliferative CD8 T cell response after neoadjuvant nivolumab plus chemotherapy treatment, suggesting systemic immune suppression. At baseline, ovarian cancer without recurrence have more terminally differentiated effector-like CD8 T cells, and patients with recurrence have more naive-like cells. Thus, both high and low TMB gynecological tumors have distinct immune landscapes associated with clinical response. Additionally, in MSI-H uterine endometrial cancer patients, the length of time between the prior chemotherapy and the initiation of immunotherapy was negatively correlated with T cell reinvigoration post immunotherapy and clinical response. This suggests the importance of optimize therapeutic timing to maximize the therapeutic efficacy when combining immunotherapy and chemotherapy.ConclusionsCollectively, our immune profiling revealed the distinct immune signatures associated with clinical response to PD-1 blockade in gynecological cancers. Our results also suggest that TMBhi inflamed versus TMBlo cold tumor microenvironment, and timing of chemo/immunotherapy could impact differentiation and functions of T cells.Ethics ApprovalThe study was approved by MSKCC Ethics Board, approval number 17–180 and 17–182.
Exhausted CD8 T (Tex) cells are immunotherapy targets in chronic infection and cancer, but a comprehensive assessment of Tex cell diversity in human disease is lacking. Here, we developed a ...transcriptomic- and epigenetic-guided mass cytometry approach to define core exhaustion-specific genes and disease-induced changes in Tex cells in HIV and human cancer. Single-cell proteomic profiling identified 9 distinct Tex cell clusters using phenotypic, functional, transcription factor, and inhibitory receptor co-expression patterns. An exhaustion severity metric was developed and integrated with high-dimensional phenotypes to define Tex cell clusters that were present in healthy subjects, common across chronic infection and cancer or enriched in either disease, linked to disease severity, and changed with HIV therapy. Combinatorial patterns of immunotherapy targets on different Tex cell clusters were also defined. This approach and associated datasets present a resource for investigating human Tex cell biology, with implications for immune monitoring and immunomodulation in chronic infections, autoimmunity, and cancer.
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•Unbiased identification of unique Tex genes using transcriptomics and epigenomics•High-dimensional CyTOF profiling of human Tex gene products reveals heterogeneity•Identification of key disease-relevant Tex cell populations in HIV and lung cancer•Development of exhaustion metrics applicable to human immune monitoring
Exhausted T (Tex) cells have poor function in chronic infections and cancer but can be therapeutically re-invigorated. Bengsch et al. use genes modified epigenetically during exhaustion and high-dimensional CyTOF profiling to define Tex cell heterogeneity in humans with HIV or lung cancer and link Tex cell features to disease progression and response to immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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