# Genetic contributions to T cell mediated immunopathology after viral infection

> **NIH NIH R21** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2020 · $189,387

## Abstract

Project Summary
From persistent infection to cancer, the ability to modulate T cell responses to alleviate disease has become
critical. One such type of intervention, immunotherapy (or checkpoint inhibition), is a relatively recent treatment
for some cancers and relies on the ability to enhance cancer-specific T cell responses. The mechanisms
underlying several of these treatments were discovered using mice persistently infected with lymphocytic
choriomeningitis virus (LCMV). As with certain cancers, negative immune regulators (NIRs, e.g. PD-1, IL-10)
are upregulated in LCMV infected mice, leading to a hypofunctional, exhausted T cell response and failure to
clear the viral infection. Blocking these NIRs relieve T cell exhaustion and lead to viral clearance. We recently
discovered that type-I interferons (IFN-I), specifically IFN-β, are the master regulators of NIRs. Blocking IFN-I
signaling leads to decreased NIR, increased T cell function, and early viral clearance. While NIR blockade in
mice persistently infected with LCMV invariably leads to the reversal of T cell exhaustion and early viral
clearance, this is not the case in humans, where only 20-70% of cases respond to immunotherapy. We have
identified several strains of mice that die when infected with the same strain and dose of LCMV and by the same
route as the persistently infected mice strains used to study the effect of NIRs on T cells. These mice also highly
express IFN-I and NIRs but instead of an exhausted T cell response, we observed a robust and
immunopathologic T cell response that leads to lysis of infected endothelial cells, vascular permeability and
death after 6-9 days of infection. Importantly, we see no differences in viral control (similar viral titers in days 1,
2, 3, and 5) when compared to persistently infected mice, suggesting that early viral dissemination that is critical
for establishing a persistent infection is not different between mice that die and those that survive with a persistent
LCMV infection. By selective breeding and phenotyping of these two groups of mice, we seek to identify the
genetic contributors that control T cell responses despite the presence of negative immune regulators. Once
uncovered, these genetic regulators of immune responses may shed light on why some respond the checkpoint
therapy while others do not, reveal novel mechanisms controlling T cell function, and lead to novel therapies to
alter T cell responses to increase patient survival.

## Key facts

- **NIH application ID:** 10310835
- **Project number:** 7R21AI145374-03
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Brian Martin Sullivan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $189,387
- **Award type:** 7
- **Project period:** 2019-07-19 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310835

## Citation

> US National Institutes of Health, RePORTER application 10310835, Genetic contributions to T cell mediated immunopathology after viral infection (7R21AI145374-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10310835. Licensed CC0.

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