Cell-intrinsic role of caspase-1 in regulating antigen-specific CD8+ T cell responses
Cell-intrinsic role of caspase-1 in regulating antigen-specific CD8+ T cell responses
批准号:
10171780
负责人:
Mehul Shamal Suthar
金额:
$21.74万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-06-01 至 2023-05-31
关键词:
AcuteAdaptor Signaling ProteinAddressAdoptive TransferAnatomyAntigensAntiviral AgentsBioenergeticsBiological AssayBrainCASP1 geneCD28 geneCD3 AntigensCD8-Positive T-LymphocytesCaspaseCell physiologyCellsCleaved cellComplexConsequentialismCuesCytosolEncephalitisEnzyme PrecursorsEpidemicGene Expression ProfilingHomingImmunityImmunologicsIn VitroInfectionInflammasomeInflammationInflammatoryInterleukin-1 betaInterleukin-18KineticsLinkMediatingMetabolismMitochondriaModelingMolecularNeuraxisNeuronal InjuryNeuronsOxidative PhosphorylationPhasePlayProductionReactive Oxygen SpeciesReceptor SignalingRegulationReportingResolutionRespirationRoleSignal TransductionSkinSpleenT cell responseT memory cellT-Cell ActivationT-Cell ReceptorT-Lymphocyte SubsetsTimeTissuesViralVirusVirus DiseasesVirus ReplicationWest Nile viral infectionWest Nile virusbasecytokinein vitro Assayin vivolymph nodesmosquito-bornemouse modelneurotropicnovelpreventprotein complex
中文摘要
摘要
英文摘要
ABSTRACT
Caspase-1 is an essential component of the inflammasome complex and is responsible for cleaving pro-
inflammatory cytokines IL-1β and IL-18 and initiating pyroptosis through cleavage of Gasdermin D. Using a
murine model of West Nile virus (WNV) infection, we and others have previously demonstrated the importance
of inflammasome signaling for promoting IL-1β-mediated protective immunity. We have now extended these
observations and discovered a novel, cell-intrinsic role for caspase-1 in regulating antigen-specific CD8+ T cells
responses during WNV infection. The absence of CD8+ T cells leads to uncontrolled WNV replication and
significant neuronal injury within the brain. To understand how environmental cues within the brain impact T cell
responses during WNV infection, we performed transcriptional profiling on antigen-specific CD8+ T cells isolated
from the spleen and brain at early and late times post-WNV infection. Through this analysis, we found that
caspase-1, as well as other inflammasome signaling components, were enriched within brain-resident antigen-
specific CD8+ T cells as compared to antigen-specific CD8+ T cells isolated from the spleen. We confirmed that
active caspase-1 is more abundantly expressed within brain-resident CD8+ T cells as compared to splenic CD8+
T cells. Using a co-adoptive transfer model, we observed increased antigen-specific Casp1-/- CD8+ T cells as
compared to WT CD8+ T cells within the spleen and brain during infection. Of note, CD8+ T cells are not infected
by WNV, suggesting that the activation of caspase-1 is independent of virus infection. Next, we characterized
caspase-1 function in vitro using an in vitro T cell receptor (TCR) stimulation assay and found that caspase-1 is
autoproteolytically cleaved following CD3/CD28 stimulation. Moreover, we found that ASC, but not NLRP3 or IL-
1β, is expressed in naïve and stimulated CD8+ T cells. Lastly, recent studies have linked caspase-1 with
mitochondrial function. Consistent with these observations, we found that αCD3/αCD28 primed Casp1-/- CD8+
T cells displayed enhanced oxidative phosphorylation as compared to WT CD8+ T cells, suggesting that
caspase-1 may regulate CD8+ T cell function by reprogramming mitochondrial dynamics and metabolism. Based
on these findings, we hypothesize that TCR stimulation of CD8+ T cells triggers caspase-1 activation, which
functions to limit T cell activation, mitochondrial bioenergetics, and cell expansion in a tissue-specific manner. In
turn, we believe that active caspase-1 is critically required for controlling virus replication within the CNS and
minimizing consequential neuronal damage by preventing an over-exuberant T cell response during viral
infection. To address this hypothesis, we have two specific aims: 1) How does caspase-1 mediate CD8+ T cell
responses during WNV infection? and 2) Aim 2. What are the molecular mechanisms of caspase-1 function
in activated CD8+ T cells? The completion of these aims will provide us with a broader understanding of the
underlying mechanisms by which caspase-1 regulates CD8+ T cells responses during virus infection.
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依托单位: