# The Cellular and Transcriptional Control of CD8 T Cell Functional Adaptation to Chronic Viruses

> **NIH NIH R01** · VERSITI BLOOD HEALTH, INC. · 2020 · $417,500

## Abstract

Chronic viral infections such as HIV and HCV affecting millions of people globally are difficult to cure.
Successful eradication of chronic viruses greatly depends on robust and long-lasting CD4 and CD8 T cell
responses. Although virus-specific CD8 T cells gradually reduce their ability to produce effector cytokines and
upregulate inhibitory receptor PD-1 in the face of persistent infection (commonly referred to as exhaustion),
several studies, including the remarkable therapeutic effects achieved by PD-1 blockade, suggest that
phenotypically “exhausted” T cells can mediate a crucial level of pathogen control. In contrast to the presently
accepted view of progressive deterioration, we propose here that virus-specific CD8 T cells stably adjust their
lineage specification and undergo a functional adaptation, which is optimized to fulfill a certain level of effector
function and pathogen control without causing overwhelming immunopathology. This new concept is further
supported by our preliminary data. We have recently found that novel cellular and signaling pathways, which
connect CD4-derived IL-21 to BATF-IRF4-STAT3 regulated transcriptional machinery in CD8 T cells,
vigorously promote the early-to-late phase developmental transition in virus-specific CD8 T cells. Based on
these new findings, we hypothesize that elevated inflammatory cytokines (such as IL-21) and persistent
antigen as hallmarks of chronic viral infection are tightly coupled through IL-21-STAT3-BATF and Antigen-
TCR-IRF4 pathways, which converge on a transcriptional level to collaboratively regulate gene expression.
Supporting this idea, our computational analyses have revealed that BATF and IRF4 cooperatively bind to the
cis-regulatory elements of multiple genes associated with the late phase effector signatures. Intriguingly, many
of these BATF-IRF4 compound-binding elements are adjacent to STAT3 binding sites, which provide the
structural basis of BATF-dependent STAT3 binding and transcriptional activation as evidenced in our
preliminary studies. Together, these lead us to propose a provocative model, in which BATF and IRF4 form a
central regulatory hub to modulate chromatin accessibility and cooperate with STAT3 to regulate the central
transcriptional networks that govern the late phase effector CD8 T cell differentiation and function. In this grant,
we will use state-of-the-art techniques to elucidate (1) which subset of CD4 T cells provides “help” to sustain
the effector function in CD8 T cells, (2) whether temporally regulated BATF expression and antigen dependent
IRF4 expression are cooperatively required for CD8 effector T cell differentiation at the late phase of chronic
infection, and (3) how BATF-IRF4 complex cooperates with JAK-STATs pathways on the epigenetic level to
confer a distinct cell-fate specification in late effector CD8 T cells. Overall, this work will provide mechanistic
insights into how CD8 T cells integrate the cellular, molecular and genetic signals to ...

## Key facts

- **NIH application ID:** 9917687
- **Project number:** 5R01AI125741-05
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** WEIGUO CUI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,500
- **Award type:** 5
- **Project period:** 2016-05-16 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917687

## Citation

> US National Institutes of Health, RePORTER application 9917687, The Cellular and Transcriptional Control of CD8 T Cell Functional Adaptation to Chronic Viruses (5R01AI125741-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9917687. Licensed CC0.

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