# CD4 T cell dysfunction and reprogramming during sepsis

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2021 · $387,083

## Abstract

Sepsis remains a major cause of death worldwide (11 million sepsis-related deaths were reported in 2017),
and that costs associated with treating septic patients place a large burden on the healthcare industry. Sepsis
is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Early stages of
sepsis are marked by hyperinflammation driven by proinflammatory cytokines (i.e., IL-1β, IL-6, IFNγ, and TNF).
Patients who survive the acute phase of sepsis display long-term impairments in immune function. This state of
chronic immunoparalysis renders sepsis survivors increasingly susceptible to secondary infections.
Consequently, there is a desperate need to better understand the cellular and molecular basis of acute sepsis
pathophysiology and subsequent immune reprogramming that defines the prolonged immune suppression.
CD4 T cells, essential for coordinating the cellular and humoral immune response to a range of pathogens
under normal circumstances, are severely depleted during the acute stage of sepsis. The overall number of
CD4 T cells gradually recover over time, but their functional capacity remains blunted for many months. For the
past 10 years, we have focused our research to pursue the long-term goal of understanding how sepsis
impacts the CD4 T cell compartment because of the key role played by CD4 T cells in the overall fitness of the
immune system. We will continue our investigation of the cellular and molecular reprogramming of CD4 T cells
during sepsis in three interconnected areas of future research: 1) Define the mechanism(s) by which regulatory
CD4 T (Treg) cells expand during sepsis; 2) Perform an integrated discovery approach using genomics,
proteomics, and metabolomics to elucidate the molecular basis of sepsis pathophysiology and CD4 T cell
immunoparalysis; and 3) Determine how intestinal microbiota dysfunction during sepsis affects the magnitude
of the cytokine storm and promotes CD4 T cell immunoparalysis and increased incidence of late-onset
mortality. We will interrogate samples obtained from multiple cohorts of sepsis patients, as well as from
preclinical mouse models of sepsis at the level of Ag-specific CD4 T cell populations. Our preclinical studies
will be further strengthened by using a novel mouse model that mimics a critical aspect of human biology –
exposure to multiple ongoing and resolved infections trains the immune system for robust responses to new
pathogens – and will serve as an important and novel ‘transitional translational’ preclinical bridge between
humans and SPF laboratory mice to mechanistically study CD4 T cell dysfunction and reprogramming during
sepsis. Addressing these key gaps in knowledge regarding the effect of sepsis on CD4 T cell biology will likely
reveal new points of intervention that can be exploited in the future to restore CD4 T cell-mediated immunity,
and overall immune fitness, following sepsis.

## Key facts

- **NIH application ID:** 10167463
- **Project number:** 1R35GM140881-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Thomas S Griffith
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,083
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167463

## Citation

> US National Institutes of Health, RePORTER application 10167463, CD4 T cell dysfunction and reprogramming during sepsis (1R35GM140881-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10167463. Licensed CC0.

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