Natural genetic variation reveals key features of epigenetic and transcriptional memory in virus-specific CD8 T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE126770 | GEO | 2019/05/21
REPOSITORIES: GEO
Similar Datasets
Project description:Inducing the long-term protection via effector memory CD8+ T cells residing in the peripheral tissues is the ultimate goal of T cell-based vaccination strategies. CD8+ T cell reacting against a particular set of antigenic peptides show propensity to generate stable pools of memory inflating cells with profound protective capacity. While the epitopes that induce memory inflation have been thoroughly characterized and used as excellent constituents of vaccines such as recombinant adenoviruses, the identity of the tissue factors responsible for maintaining memory inflating CD8+ T cells remains elusive. Here, we have used a Cre recombinase-dependent, -galactosidase (gal)–recombinant adenovirus vector that allowed for cell-specific expression of gal epitopes and identification of cell types involved in generation of inflationary responses. While targeting antigen expression to classical hematopoietic antigen presenting cells was insufficient to activate gal-specific CD8+ T cells, expressing the antigen exclusively in CCL19-producing fibroblastic stromal cells (FSCs) induced robust anti-gal CD8+ T cell response. Using bone marrow chimera mice to abolish the expression of major histocompatibility complex I (MHC-I) and Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF3) in hematopoietic cells we demonstrated that CCL19-expressing FCS function as antigen libraries, gradually releasing the antigen to CD103+ DCs to maintain gal-specific memory inflating population. Moreover, targeted ablation of CCL19-producing cells revealed that pulmonary fibroblastic stromal cells act as the principal organizer of the nurturing niches that support the metabolic conversion in CD8+ T cells necessary for the generation of long-lasting protective inflationary responses. Overall, our data reveal a hitherto unknown function of CCL19-expressiong fibroblastic stromal in supporting the metabolic fitness of CD8+ T cells, thereby promoting the generation of tissue-specific and long-lasting protective CD8+ T cell responses.
2021-05-25 | E-MTAB-9558 | biostudies-arrayexpress
Project description:Inducing the long-term protection via effector memory CD8+ T cells residing in the peripheral tissues is the ultimate goal of T cell-based vaccination strategies. CD8+ T cell reacting against a particular set of antigenic peptides show propensity to generate stable pools of memory inflating cells with profound protective capacity. While the epitopes that induce memory inflation have been thoroughly characterized and used as excellent constituents of vaccines such as recombinant adenoviruses, the identity of the tissue factors responsible for maintaining memory inflating CD8+ T cells remains elusive. Here, we have used a Cre recombinase-dependent, -galactosidase (gal)–recombinant adenovirus vector that allowed for cell-specific expression of gal epitopes and identification of cell types involved in generation of inflationary responses. While targeting antigen expression to classical hematopoietic antigen presenting cells was insufficient to activate gal-specific CD8+ T cells, expressing the antigen exclusively in CCL19-producing fibroblastic stromal cells (FSCs) induced robust anti-gal CD8+ T cell response. Using bone marrow chimera mice to abolish the expression of major histocompatibility complex I (MHC-I) and Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF3) in hematopoietic cells we demonstrated that CCL19-expressing FCS function as antigen libraries, gradually releasing the antigen to CD103+ DCs to maintain gal-specific memory inflating population. Moreover, targeted ablation of CCL19-producing cells revealed that pulmonary fibroblastic stromal cells act as the principal organizer of the nurturing niches that support the metabolic conversion in CD8+ T cells necessary for the generation of long-lasting protective inflationary responses. Overall, our data reveal a hitherto unknown function of CCL19-expressiong fibroblastic stromal in supporting the metabolic fitness of CD8+ T cells, thereby promoting the generation of tissue-specific and long-lasting protective CD8+ T cell responses.
2021-05-25 | E-MTAB-9580 | biostudies-arrayexpress
Project description:<p>The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving the changes characteristic of immune aging in humans remain poorly understood. One hallmark of immune aging is the loss of self-renewing naive cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we first inferred the transcription factor binding activities that maintain the naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we determined that BATF, ETS1, Eomes, and Sp1 govern transcription networks associated with specific CD8 T cell subset properties, including activation and proliferative potential. Extending our analysis to aged humans, we found that the differences between memory and naive CD8 T cells were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward a more differentiated pattern of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin openness at gene promoters, a phenomenon that appears to be due largely to a loss in binding by NRF1, leading to a marked drop-off in the ability of the naive cell to initiate transcription of mitochondrial genes. Our findings identify BATF- and NRF1-driven gene regulation as targets for delaying CD8 T cell aging and restoring T cell function.</p>
| phs001187 | dbGaP
Project description:Anti-viral CD8 T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells (cDC1), which in turn are critical for the optimal priming of CD8 T cells. Here we show that BATF3 is expressed within the first days after priming but has long-lasting T cell intrinsic effects. We found that T cells that lack Batf3 show a normal expansion and differentiation, yet succumbed to an aggravated contraction and had a diminished memory response. Vice versa BATF3-overexpression in CD8 T cells promoted their survival and transition to memory. Mechanistically, BATF3 regulates T cell apoptosis and longevity via the proapoptotic factor BIM. By programing CD8 T cell survival and memory, BATF3 is a promising molecule to optimize adoptive T cell therapy in patients.
2020-08-31 | GSE143504 | GEO
Project description:Anti-viral CD8 T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells (cDC1), which in turn are critical for the optimal priming of CD8 T cells. Here we show that BATF3 is expressed within the first days after priming but has long-lasting T cell intrinsic effects. We found that T cells that lack Batf3 show a normal expansion and differentiation, yet succumbed to an aggravated contraction and had a diminished memory response. Vice versa BATF3-overexpression in CD8 T cells promoted their survival and transition to memory. Mechanistically, BATF3 regulates T cell apoptosis and longevity via the proapoptotic factor BIM. By programing CD8 T cell survival and memory, BATF3 is a promising molecule to optimize adoptive T cell therapy in patients.
2020-08-31 | GSE153341 | GEO
Project description:Memory CD8+ T cells have the ability to provide lifelong immunity against pathogens. Although memory features generally arise after challenge with a foreign antigen, naïve CD8 single positive (SP) thymocytes may acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4. This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). However, the underlying molecular mechanisms remain ill-defined. Using epigenomic profiling, we show that these innate memory CD8SP cells acquire only a portion of the active enhancer repertoire of conventional memory cells. This reprograming is secondary to EOMES recruitment, mostly to RUNX3-bound enhancers. Furthermore, EOMES is found within chromatin-associated complexes containing BRG1 and promotes the recruitment of this chromatin remodelling factor. Also, the in vivo acquisition of EOMES-dependent program is BRG1-dependent. In conclusion, our results support a strong epigenetic basis for the EOMES-driven establishment of CD8+ T cell innate memory program.
2019-06-06 | PXD014142 | Pride
Project description:This data is from a murine model established to study the lasting impact of allergic airway sensitization on subsequent anti-viral memory T cell responses and the ability to develop protective immunity to reinfection. Animals were either sensitised by exposure to HDM or PBS and then subsequently exposed to influenza virus. Samples were collected at various time points for analysis of both CD8 and C4 positive tissue resident memory T cells.
2023-01-30 | E-MTAB-11116 | biostudies-arrayexpress
Project description:CD8 T cell memory differentiation endows T cells with an ability to rapidly induce effector functions upon pathogen re-encounter. While it is well established that substantial epigenetic remodeling occurs during the effector stage of the immune response, the signaling events that imprint CD8 T cells with these stable epigenetic programs are not well-defined. To gain insight into the signaling determinants of effector-associated epigenetic programming among CD8 T cells, we explored the role of IL-12 in the imprinting of IFNg expression during human CD8 T cell priming. We observe that anti-CD3/CD28-mediated stimulation of human naïve CD8 T cells is not sufficient to induce substantial demethylation of the IFNg promotor. However, anti-CD3/CD28 stimulation in the presence of the inflammatory cytokine, IL-12, resulted in significant and stable demethylation of the IFNg locus that was commensurate with an increase in IFNg expression. We further show that IL-12-associated demethylation of the IFNg locus is coupled to cell division through TET2-dependent demethylation in an ex vivo human CAR T cell model system and an in vivo immunologically competent murine system. Collectively, these data illustrate that IL-12 signaling promotes TET2-mediated effector epigenetic programming in CD8 T cells during the primary immune response and serve as proof of concept that signal 3 cytokines can be used to guide the induction of epigenetically regulated traits among T cells used for adoptive immunotherapies.
2021-08-31 | GSE182968 | GEO
Project description:T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial – but not complete – normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes.
2023-07-19 | GSE237729 | GEO
Project description:Exhausted CD8 T cells result from chronic antigen stimulation and have reduced ability to clear disease. The epigenetic regulation of the dysfunctional phenotype of exhausted CD8 T cells is a promising avenue for therapies aimed at reversing or preventing CD8 T cell exhaustion. Here, utilizing an in vitro model, we show global increase of the repressive histone modification H3K27me3 in CD8 T cell exhaustion as well as increased gene expression of the subunits of PRC2, the complex responsible for H3K27me3 deposition. H3K27me3 correlated with decreased gene expression and localized to naïve/memory T cell genes in CD8 T cell exhaustion. PRC2 inhibition increased expression of many of these naïve/memory genes while reducing expression of key exhaustion genes. Further, we identified potential enhancers and transcription factors predicted to promote expression of the PRC2 subunits. Our study highlights the importance of the repressive epigenetic landscape of exhausted CD8 T cells as well as a novel role for PRC2 in T cell biology.
2024-10-31 | GSE263937 | GEO