RasGRP1 Regulates Antigen-Induced Developmental Programming by Naive CD8 T Cells

Priatel, John J.; Chen, Xiaoxi; Huang, Yu-Hsuan; Chow, Michael; Zenewicz, Lauren A.; Coughlin, Jason J.; Shen, Hao; Stone, James C.; Tan, Rusung; Teh, Hung Sia

doi:10.4049/jimmunol.0803521

Cited by 21 publications

(21 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Positive selection of thymocytes with relative high affinity to self-peptide-MHC complex, including regulatory T cells and some innate CD8 T cells, is less dependent on RasGRP1 (42, 43). We have demonstrated here that RasGRP1 plays crucial roles in i NKT cell development and is important for the generation and/or maintenance of CD4 + i NKT cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Critical Roles of RasGRP1 for Invariant NKT Cell Development

Shen

Chen

Gorentla

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The invariant NKT (iNKT) cell lineage contains CD4+ and CD4- subsets. The mechanisms that control such subset differentiation and iNKT cell maturation in general have not been fully understood. RasGRP1, a guanine nucleotide exchange factor for T cell receptor-induced activation of the Ras-Erk1/2 pathway, is critical for conventional αβ T cell development but dispensable for generating regulatory T cells. Its role in iNKT cells has been unknown. Here we report severe decreases of iNKT cells in RasGRP1-/- mice through cell intrinsic mechanisms. In the remaining iNKT cells in RasGRP1-/- mice, there is a selective absence of the CD4+ subset. Furthermore, RasGRP1-/- iNKT cells are defective in T cell receptor induced proliferation in vitro. These observations establish that RasGRP1 is not only important for early iNKT cell development, but also for the generation/maintenance of the CD4+ iNKT cells. Our data provides genetic evidence that the CD4+ and CD4- iNKT cells are distinct sub-lineages with differential signaling requirements for their development.

show abstract

Section: Discussionmentioning

confidence: 99%

Critical Roles of RasGRP1 for Invariant NKT Cell Development

Shen

Chen

Gorentla

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thymidine incorporation assays and CFSE labeling were performed as described previously. 48,49 For blocking experiments, B cell, non-B cell and B lymphoma APCs were pre-coated with 10 mg/mL of SLAM family receptor CD48 (HM48-1), Ly9 and Ly108 antibodies or isotype-matched control antibodies for 1 h at 37 C. …”

Section: Sh2d1amentioning

confidence: 99%

2B4-SAP signaling is required for the priming of naive CD8⁺ T cells by antigen-expressing B cells and B lymphoma cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8C T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a¡/¡ CD8 C T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a¡/¡ CD8 C T cells responded equivalently to wild-type CD8 C T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8 C T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8 C T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8C T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.

show abstract

“…Furthermore, we found locus-specific GO categories such as "T-cell differentiation" for RASGRP1, consistent with the role of Rasgrp1 in T-cell signaling (15), and "microtubule-based process" for RRAS2, supporting its role in the regulation of cytoskeleton and its participation in related function such as adhesion, migration, and invasion (16).…”

Section: P19mentioning

confidence: 50%

Identifying regulatory mechanisms underlying tumorigenesis using locus expression signature analysis

Lee

Ridder

Kool³

et al. 2014

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

View full text Add to dashboard Cite

Retroviral insertional mutagenesis is a powerful tool for identifying putative cancer genes in mice. To uncover the regulatory mechanisms by which common insertion loci affect downstream processes, we supplemented genotyping data with genome-wide mRNA expression profiling data for 97 tumors induced by retroviral insertional mutagenesis. We developed locus expression signature analysis, an algorithm to construct and interpret the differential gene expression signature associated with each common insertion locus. Comparing locus expression signatures to promoter affinity profiles allowed us to build a detailed map of transcription factors whose protein-level regulatory activity is modulated by a particular locus. We also predicted a large set of drugs that might mitigate the effect of the insertion on tumorigenesis. Taken together, our results demonstrate the potential of a locus-specific signature approach for identifying mammalian regulatory mechanisms in a cancer context. genome-wide expression profiling | transcription factor activity | gene regulatory network | computational cancer biology | data integration M ouse retroviral insertional mutagenesis has been used as an efficient tool for identification of causal mutations in cancer (1). Such oncogenic mutations may either cause alteration of a gene product or influence the expression levels of one or more genes surrounding the insertion. More than 10,000 common insertion sites (CISs) at which retroviral insertions are found in multiple tumors have been identified (2). Methods exist that predict which genes are affected by insertions based on information such as orientation and position (3). However, it is not always straightforward to determine which genetic lesions near a CIS are playing a causal role. Moreover, these approaches are based on gene annotation and do not use or provide functional evidence. Analyzing the mRNA expression level of the genes near the insertion site is often not sufficient, as the lesion may exert its effect only at the posttranslational level. Furthermore, retroviral insertional mutagenesis screens alone rarely elucidate the regulatory mechanisms that drive tumorigenesis. These limitations highlight the need for new approaches that can integrate the genetic data with functional genomics data and other information to identify causal genes and regulatory mechanisms underlying cancer.Here, we carried out genome-wide expression profiling in a set of tumors induced by retroviral insertional mutagenesis. We also present a computational approach, locus expression signature analysis (LESA), that first defines and then analyzes the genome-wide mRNA expression response induced by the putative causal gene near the insertion locus. We analyzed genome-wide expression profiles for a panel of splenic tumors induced by retroviral insertional mutagenesis (3). To identify regulatory mechanisms underlying tumorigenesis, we hypothesized that gene expression is affected by insertional mutations through the regulation by sequence specific transcription ...

show abstract

RasGRP1 Regulates Antigen-Induced Developmental Programming by Naive CD8 T Cells

Cited by 21 publications

References 58 publications

Critical Roles of RasGRP1 for Invariant NKT Cell Development

Critical Roles of RasGRP1 for Invariant NKT Cell Development

2B4-SAP signaling is required for the priming of naive CD8⁺ T cells by antigen-expressing B cells and B lymphoma cells

Identifying regulatory mechanisms underlying tumorigenesis using locus expression signature analysis

Contact Info

Product

Resources

About

RasGRP1 Regulates Antigen-Induced Developmental Programming by Naive CD8 T Cells

Cited by 21 publications

References 58 publications

Critical Roles of RasGRP1 for Invariant NKT Cell Development

Critical Roles of RasGRP1 for Invariant NKT Cell Development

2B4-SAP signaling is required for the priming of naive CD8+ T cells by antigen-expressing B cells and B lymphoma cells

Identifying regulatory mechanisms underlying tumorigenesis using locus expression signature analysis

Contact Info

Product

Resources

About

2B4-SAP signaling is required for the priming of naive CD8⁺ T cells by antigen-expressing B cells and B lymphoma cells