NFAT signaling is indispensable for persistent memory responses of MCMV-specific CD8+ T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228527 | GEO | 2024/01/25
REPOSITORIES: GEO
Similar Datasets
Project description:Reconstitution of cytomegalovirus (CMV)-specific immunity following transplant remains a primary clinical objective to prevent CMV disease, and adoptive immunotherapy of CMV-specific T cells can be an effective therapeutic approach. Due to the persistence of CMV, most CMV-specific CD8+ T cells become terminally differentiated effector cells (TEFF). However, a minor subset retains a memory phenotype (TM). Interestingly, recent studies suggest that CMV-specific CD8+ T cells with different phenotypes may have different abilities to reconstitute sustained immunity following transfer. The immunology of human CMV (HCMV) infections is reflected in the mouse model of MCMV infection. We found that HCMV- and MCMV-specific T cells displayed shared genetic programs, validating the MCMV model for studies of CMV-specific T cells in vivo. After transfer, the proliferative capacity of MCMV-specific TM cells was vastly superior to TEFF cells. Strikingly, TM cells expanded and established sustained and diverse T cell populations even after multiple challenges. Although both TEFF and TM cells could protect Rag-/- mice, only TM cells could consistently survive after transfer into immune replete, latently infected recipients and respond if recipient immunity was lost. These data show that CMV-specific TM cells retain memory function during persistent infection and can re-establish CMV immunity when necessary. C57BL/6 mice were infected intraperitoneally (i.p.) with MCMV strain MW97.01 between 6-16 weeks of age. Splenocytes were isolated from chronically-infected mice and co-stained with three PE-conjugated tetramers loaded with the antigenic peptides from M38, m139 and IE3, all of which promote memory inflation. Cells were then stained with fluorescently conjugated antibodies and sorted on a MoFlo cell sorter. Naïve CD8+ cells were identified as CD44lo. MCMV-specific T cells were identified as CD8+, CD44hi and tetramer binding and then further segregated into memory and effector cells subsets by their expression of KLRG1 and CD127.
2015-01-28 | E-GEOD-61927 | biostudies-arrayexpress
Project description:Reconstitution of cytomegalovirus (CMV)-specific immunity following transplant remains a primary clinical objective to prevent CMV disease, and adoptive immunotherapy of CMV-specific T cells can be an effective therapeutic approach. Due to the persistence of CMV, most CMV-specific CD8+ T cells become terminally differentiated effector cells (TEFF). However, a minor subset retains a memory phenotype (TM). Interestingly, recent studies suggest that CMV-specific CD8+ T cells with different phenotypes may have different abilities to reconstitute sustained immunity following transfer. The immunology of human CMV (HCMV) infections is reflected in the mouse model of MCMV infection. We found that HCMV- and MCMV-specific T cells displayed shared genetic programs, validating the MCMV model for studies of CMV-specific T cells in vivo. After transfer, the proliferative capacity of MCMV-specific TM cells was vastly superior to TEFF cells. Strikingly, TM cells expanded and established sustained and diverse T cell populations even after multiple challenges. Although both TEFF and TM cells could protect Rag-/- mice, only TM cells could consistently survive after transfer into immune replete, latently infected recipients and respond if recipient immunity was lost. These data show that CMV-specific TM cells retain memory function during persistent infection and can re-establish CMV immunity when necessary.
2015-01-28 | GSE61927 | GEO
Project description:We show that the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1) is dispensable for the development of naïve mouse CD8 T cells, but is necessary for the optimal expansion and production of effector molecules by antigen-specific CD8 T cells in vivo. PTBP1 has an essential role in regulating the early events following activation of the naïve CD8 T cell leading to IL-2 and TNF production. It is also required to protect activated CD8 T cells from apoptosis. PTBP1 controls alternative splicing of over 400 genes in naïve CD8 T cells in addition to regulating the abundance of ~200 mRNAs. PTBP1 is required for the nuclear accumulation of c-Fos, NFATc2 and NFATc3, but not NFATc1. This selective effect on NFAT proteins correlates with PTBP1-promoted expression of the shorter Ab1 isoform and exon 13 skipped Ab2 isoform of the catalytic A-sububit of calcineurin phosphatse. These findings reveal a crucial role for PTBP1 in regulating CD8 T cell activation.
2021-12-09 | GSE190512 | GEO
Project description:Chronic infection with cytomegalovirus (CMV) leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called ‘memory inflation’ is thought to be mainly determined by the availability of antigenic stimuli during the chronic phase of infection. However, by mapping the long-term development of CD8+ T cell families derived from single naive precursors, we find that T cell fate decisions, taken during the acute phase of murine CMV infection, can alter the level of memory inflation by more than 1000-fold. Counterintuitively, a T cell family’s capacity for memory inflation is not determined by its initial clonal expansion. Instead, those rare T cell families that strongly dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family’s long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem cell-like source for the antigen-driven maintenance of memory inflation.
2020-09-05 | GSE157501 | GEO
Project description:Chronic infection with cytomegalovirus (CMV) leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called ‘memory inflation’ is thought to be mainly determined by the availability of antigenic stimuli during the chronic phase of infection. However, by mapping the long-term development of CD8+ T cell families derived from single naive precursors, we find that T cell fate decisions, taken during the acute phase of murine CMV infection, can alter the level of memory inflation by more than 1000-fold. Counterintuitively, a T cell family’s capacity for memory inflation is not determined by its initial clonal expansion. Instead, those rare T cell families that strongly dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family’s long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem cell-like source for the antigen-driven maintenance of memory inflation.
2020-09-09 | GSE157641 | GEO
Project description:Reactivation of latent HCMV is a significant infectious complication of organ transplantation, and current therapies target viral replication once reactivation of transcriptionally silent, latent virus has already occurred. The specific molecular pathways that activate viral gene expression are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. MCMV is a valuable model for studying latency and reactivation of CMV induced by organ transplantation. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces transcriptional reactivation of immediate early (IE) gene expression within 48 hr. We used microarrays to profile global mouse kidney gene expression associated with transcriptional reactivation of MCMV immediate early gene expression at 48 hr after transplant of MCMV latently infected kidneys into allogeneic recipients. We identified differentially expressed genes and pathways associated with both early acute rejection and reactivation of MCMV. control vs. allograft
2015-08-27 | E-GEOD-72392 | biostudies-arrayexpress
Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Determination of NFAT1 binding sites in CD8 T cells in vitro
2015-02-13 | E-GEOD-64407 | biostudies-arrayexpress
Project description:This a model from the article:
Dynamics of killer T cell inflation in viral infections.
Wodarz D, Sierro S, Klenerman P. J R Soc Interface
2007 Jun 22;4(14):533-43 17251133
,
Abstract:
Upon acute viral infection, a typical cytotoxic T lymphocyte (CTL) response is
characterized by a phase of expansion and contraction after which it settles at
a relatively stable memory level. Recently, experimental data from mice infected
with murine cytomegalovirus (MCMV) showed different and unusual dynamics. After
acute infection had resolved, some antigen specific CTL started to expand over
time despite the fact that no replicative virus was detectable. This phenomenon
has been termed as "CTL memory inflation". In order to examine the dynamics of
this system further, we developed a mathematical model analysing the impact of
innate and adaptive immune responses. According to this model, a potentially
important contributor to CTL inflation is competition between the specific CTL
response and an innate natural killer (NK) cell response. Inflation occurs most
readily if the NK cell response is more efficient than the CTL at reducing virus
load during acute infection, but thereafter maintains a chronic virus load which
is sufficient to induce CTL proliferation. The model further suggests that
weaker NK cell mediated protection can correlate with more pronounced CTL
inflation dynamics over time. We present experimental data from mice infected
with MCMV which are consistent with the theoretical predictions. This model
provides valuable information and may help to explain the inflation of CMV
specific CD8+T cells seen in humans as they age.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Wodarz D, Sierro S, Klenerman P. (2007) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2010-06-25 | BIOMD0000000688 | BioModels
Project description:This a model from the article:
Dynamics of killer T cell inflation in viral infections.
Wodarz D, Sierro S, Klenerman P. J R Soc Interface
2007 Jun 22;4(14):533-43 17251133
,
Abstract:
Upon acute viral infection, a typical cytotoxic T lymphocyte (CTL) response is
characterized by a phase of expansion and contraction after which it settles at
a relatively stable memory level. Recently, experimental data from mice infected
with murine cytomegalovirus (MCMV) showed different and unusual dynamics. After
acute infection had resolved, some antigen specific CTL started to expand over
time despite the fact that no replicative virus was detectable. This phenomenon
has been termed as "CTL memory inflation". In order to examine the dynamics of
this system further, we developed a mathematical model analysing the impact of
innate and adaptive immune responses. According to this model, a potentially
important contributor to CTL inflation is competition between the specific CTL
response and an innate natural killer (NK) cell response. Inflation occurs most
readily if the NK cell response is more efficient than the CTL at reducing virus
load during acute infection, but thereafter maintains a chronic virus load which
is sufficient to induce CTL proliferation. The model further suggests that
weaker NK cell mediated protection can correlate with more pronounced CTL
inflation dynamics over time. We present experimental data from mice infected
with MCMV which are consistent with the theoretical predictions. This model
provides valuable information and may help to explain the inflation of CMV
specific CD8+T cells seen in humans as they age.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Wodarz D, Sierro S, Klenerman P. (2007) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2010-06-25 | BIOMD0000000687 | BioModels
Project description:This a model from the article:
Dynamics of killer T cell inflation in viral infections.
Wodarz D, Sierro S, Klenerman P. J R Soc Interface
2007 Jun 22;4(14):533-43 17251133
,
Abstract:
Upon acute viral infection, a typical cytotoxic T lymphocyte (CTL) response is
characterized by a phase of expansion and contraction after which it settles at
a relatively stable memory level. Recently, experimental data from mice infected
with murine cytomegalovirus (MCMV) showed different and unusual dynamics. After
acute infection had resolved, some antigen specific CTL started to expand over
time despite the fact that no replicative virus was detectable. This phenomenon
has been termed as "CTL memory inflation". In order to examine the dynamics of
this system further, we developed a mathematical model analysing the impact of
innate and adaptive immune responses. According to this model, a potentially
important contributor to CTL inflation is competition between the specific CTL
response and an innate natural killer (NK) cell response. Inflation occurs most
readily if the NK cell response is more efficient than the CTL at reducing virus
load during acute infection, but thereafter maintains a chronic virus load which
is sufficient to induce CTL proliferation. The model further suggests that
weaker NK cell mediated protection can correlate with more pronounced CTL
inflation dynamics over time. We present experimental data from mice infected
with MCMV which are consistent with the theoretical predictions. This model
provides valuable information and may help to explain the inflation of CMV
specific CD8+T cells seen in humans as they age.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Wodarz D, Sierro S, Klenerman P. (2007) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2010-06-25 | BIOMD0000000686 | BioModels