# Cell-intrinsic role of caspase-1 in regulating antigen-specific CD8+ T cell responses

> **NIH NIH R21** · EMORY UNIVERSITY · 2020 · $262,535

## Abstract

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...

## Key facts

- **NIH application ID:** 10048501
- **Project number:** 1R21AI154352-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Mehul Shamal Suthar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $262,535
- **Award type:** 1
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048501

## Citation

> US National Institutes of Health, RePORTER application 10048501, Cell-intrinsic role of caspase-1 in regulating antigen-specific CD8+ T cell responses (1R21AI154352-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10048501. Licensed CC0.

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