scholarly journals SRSF1 serves as a critical posttranscriptional regulator at the late stage of thymocyte development

2021 ◽  
Vol 7 (16) ◽  
pp. eabf0753
Author(s):  
Zhihong Qi ◽  
Fang Wang ◽  
Guotao Yu ◽  
Di Wang ◽  
Yingpeng Yao ◽  
...  
Keyword(s):  
T Cell ◽  
Late Stage ◽  
Gene Networks ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
Thymocyte Development ◽  
Conditional Deletion ◽  
Thymocyte Differentiation ◽  
Underlying Mechanisms

The underlying mechanisms of thymocyte maturation remain largely unknown. Here, we report that serine/arginine-rich splicing factor 1 (SRSF1) intrinsically regulates the late stage of thymocyte development. Conditional deletion of SRSF1 resulted in severe defects in maintenance of late thymocyte survival and a blockade of the transition of TCRβhiCD24+CD69+ immature to TCRβhiCD24−CD69− mature thymocytes, corresponding to a notable reduction of recent thymic emigrants and diminished periphery T cell pool. Mechanistically, SRSF1 regulates the gene networks involved in thymocyte differentiation, proliferation, apoptosis, and type I interferon signaling pathway to safeguard T cell intrathymic maturation. In particular, SRSF1 directly binds and regulates Irf7 and Il27ra expression via alternative splicing in response to type I interferon signaling. Moreover, forced expression of interferon regulatory factor 7 rectifies the defects in SRSF1-deficient thymocyte maturation via restoring expression of type I interferon–related genes. Thus, our work provides new insight on SRSF1-mediated posttranscriptional regulatory mechanism of thymocyte development.

scholarly journals Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Keigo Kawashima ◽  
Masanori Isogawa ◽  
Susumu Hamada-Tsutsumi ◽  
Ian Baudi ◽  
Satoru Saito ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Type I Interferon ◽  
T Cell Responses ◽  
Antigen Expression ◽  
Type I ◽  
Interferon Signaling ◽  
Cell Responses ◽  
B Virus

ABSTRACT Robust virus-specific CD8+ T cell responses are required for the clearance of hepatitis B virus (HBV). However, the factors that determine the magnitude of HBV-specific CD8+ T cell responses are poorly understood. To examine the impact of genetic variations of HBV on HBV-specific CD8+ T cell responses, we introduced three HBV clones (Aa_IND [Aa], C_JPN22 [C22], and D_IND60 [D60]) that express various amounts of HBV antigens into the livers of C57BL/6 (B6) (H-2b) mice and B10.D2 (H-2d) mice. In B6 mice, clone C22 barely induced HBV-specific CD8+ T cell responses and persisted the longest, while clone D60 elicited strong HBV-specific CD8+ T cell responses and was rapidly cleared. These differences between HBV clones largely diminished in H-2d mice. Interestingly, the magnitude of HBV-specific CD8+ T cell responses in B6 mice was associated with the HB core antigen expression level during the early phase of HBV transduction. Surprisingly, robust HBV-specific CD8+ T cell responses to clone C22 were induced in interferon-α/β receptor-deficient (IFN-αβR–/–) (H-2b) mice. The induction of HBV-specific CD8+ T cell responses to C22 in IFN-αβR–/– mice reflects enhanced HBV antigen expression because the suppression of antigen expression by HBV-specific small interfering RNA (siRNA) attenuated HBV-specific T cell responses in IFN-αβR–/– mice and prolonged HBV expression. Collectively, these results suggest that HBV genetic variation and type I interferon signaling determine the magnitude of HBV-specific CD8+ T cell responses by regulating the initial antigen expression levels. IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8+ T cell responses are required for the clearance of HBV. However, the relative contributions of genetic variation and innate immune responses to the induction of HBV-specific CD8+ T cell responses are not fully understood. In this study, we discovered that different clearance rates between HBV clones after hydrodynamic transduction were associated with the magnitude of HBV-specific CD8+ T cell responses and initial HB core antigen expression. Surprisingly, type I interferon signaling negatively regulated HBV-specific CD8+ T cell responses by reducing early HBV antigen expression. These results show that the magnitude of the HBV-specific CD8+ T cell response is regulated primarily by the initial antigen expression level.

scholarly journals Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function

Immunity ◽  
2019 ◽  
Vol 51 (6) ◽  
pp. 1074-1087.e9 ◽  
Author(s):  
Alexander Lercher ◽  
Anannya Bhattacharya ◽  
Alexandra M. Popa ◽  
Michael Caldera ◽  
Moritz F. Schlapansky ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Urea Cycle ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
T Cell Function

scholarly journals Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment

2018 ◽  
Vol 14 (4) ◽  
pp. e1006985 ◽  
Author(s):  
Arunakumar Gangaplara ◽  
Craig Martens ◽  
Eric Dahlstrom ◽  
Amina Metidji ◽  
Ameya S. Gokhale ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Viral Infection ◽  
Regulatory T Cell ◽  
Cell Function ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
T Cell Function

scholarly journals Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs

2016 ◽  
Vol 127 (1) ◽  
pp. 269-279 ◽  
Author(s):  
Liang Cheng ◽  
Jianping Ma ◽  
Jingyun Li ◽  
Dan Li ◽  
Guangming Li ◽  
...  
Keyword(s):  
T Cell ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
Cell Recovery ◽  
Hiv 1 ◽  
Blocking Type

scholarly journals The transcriptional repressor Bcl6 promotes pre-TCR-induced thymocyte differentiation and attenuates Notch1 activation

Development ◽  
2020 ◽  
Vol 147 (19) ◽  
pp. dev192203
Author(s):  
Anisha Solanki ◽  
Diana C. Yánez ◽  
Ching-In Lau ◽  
Jasmine Rowell ◽  
Alessandro Barbarulo ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Transcriptional Repressor ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Double Positive ◽  
Conditional Deletion ◽  
Tcr Signal Transduction ◽  
Thymocyte Differentiation ◽  
Notch Activation

ABSTRACTPre-T-cell receptor (TCR) signal transduction is required for developing thymocytes to differentiate from CD4−CD8− double-negative (DN) cell to CD4+CD8+ double-positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor Bcl6 and that Bcl6 is required for differentiation to DP. Conditional deletion of Bcl6 from thymocytes reduced pre-TCR-induced differentiation to DP cells, disrupted expansion and enrichment of intracellular TCRβ+ cells within the DN population and increased DN4 cell death. Deletion also increased Notch1 activation and Notch-mediated transcription in the DP population. Thus, Bcl6 is required in thymocyte development for efficient differentiation from DN3 to DP and to attenuate Notch1 activation in DP cells. Given the importance of inappropriate NOTCH1 signalling in T-cell acute lymphoblastic leukaemia (T-ALL), and the involvement of BCL6 in other types of leukaemia, this study is important to our understanding of T-ALL.

scholarly journals 779 Inhibiting type-I interferon signaling promotes memory T-cell formation following immunization with Listeria anti-cancer vaccines

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A814-A814
Author(s):  
Zachary Morrow ◽  
John-Demian Sauer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Type I Interferon ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Type I ◽  
Interferon Signaling ◽  
Wild Type ◽  
Cell Responses

BackgroundThe aspiration of cancer immunotherapy is to generate large numbers of highly functional anti-tumor CD8+ T-cells. We and others have optimized Listeria monocytogenes as a powerful anti-cancer vaccine platform to drive such T-cell responses. Early clinical trial data suggest the number of T-cells generated correlates with efficacy, demanding an understanding of the factors that dictate vaccine-induced T-cell responses. The CD8+ T-cell response is intimately linked to magnitude and quality of the innate immune response triggered by vaccines. Listeria-based vaccines activate numerous innate pathways and can be engineered to hyper- or hypo-induce these pathways. We sought to understand how modulating innate immunity would impact vaccine efficacy.MethodsTo dissect the impact of type I interferon signaling and the inflammasomes on L. monocytogenes induced T-cell responses, we immunized IFNAR-/-, Caspase1/11-/-, and novel IFNAR-/-Caspase1/11-/- double knockouts mice we generated for this study. CD8+ T-cell responses were assessed at the peak T-cell response, after contraction and memory formation, and after rechallenge. The phenotype and magnitude of CD8+ T-cells was assessed at each stage, and functional outcomes were assessed by measuring protection from reinfection by wild-type Listeria.ResultsIFNAR-/- mice developed the largest number of CD8+ T-cells during the peak primary response contradicting the dogma that Type-I Interferon promotes robust CD8+ T-cell responses. Caspase1/11-/- mice were not significantly different from wild-type mice. The frequency of short-lived effector cells (assessed by expression of CD127 and KLRG1) was no different between wild-type and IFNAR-/- mice, however we observed more than twice as many memory precursor cells at the peak CD8+ T-cell response. These findings extend to the memory and recall stage with more antigen-specific T-cells observed after contraction and upon rechallenge. Finally, IFNAR-/- mice are remarkably more protected from wild-type Listeria rechallenge than their counterparts after immunization demonstrating the efficacy of the increased memory T-cell pool. Data are representative of at least two independent replicates with at least 5 mice per group and significance was assessed by one-way ANOVA with *p<0.05.ConclusionsWe demonstrated that type-I interferon signaling deficiency leads to enhanced prophylactic vaccine efficacy through increased memory T-cell formation. Ultimately, for patients with slow growing tumors or with high-risk mutations, prophylactic tumor vaccines could elicit life-long protection from disease. Importantly, increased memory precursor T-cell abundance did not come at the expense of short-lived effectors leaving open the possibility that blocking Type-I IFN could potentiate lasting immunological memory in both the therapeutic and prophylactic setting.

scholarly journals Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling

2016 ◽  
Vol 17 (5) ◽  
pp. 565-573 ◽  
Author(s):  
Yan Xing ◽  
Xiaodan Wang ◽  
Stephen C Jameson ◽  
Kristin A Hogquist
Keyword(s):  
T Cell ◽  
Type I Interferon ◽  
Cell Maturation ◽  
Type I ◽  
Interferon Signaling ◽  
T Cell Maturation ◽  
Late Stages
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