# NFAT, bZIP proteins, and transcriptional programs in lymphocytes

> **NIH NIH R01** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2020 · $669,740

## Abstract

ABSTRACT
Blocking antibodies to CTLA4, PD-1, and other inhibitory surface receptors expressed on exhausted T cells, or
blocking antibodies to the PD-1 ligands PD-L1 and PD-L2 expressed by tumor and stromal cells, have been
remarkably successful at promoting long-term tumor regression. Combinations of blocking antibodies to
multiple inhibitory receptors, often reinforced with activating antibodies to costimulatory receptors, have been
more effective than treatment with individual blocking antibodies alone. Nevertheless, despite these
successes, many patients still fail to respond to `immune checkpoint blockade' therapies, emphasizing the
need to understand immune cell `exhaustion' at a molecular level, both in mouse models and in humans.
The calcium- and calcineurin-regulated transcription factor NFAT is a driver of the transcriptional responses
underlying T cell activation. The T cell activation program mainly depends on cooperative binding of NFAT and
its transcriptional partner AP1 (Fos-Jun) at composite DNA sites in gene promoters and enhancers. In parallel,
NFAT can activate a second transcriptional program that imposes a hyporesponsive state, typically termed
`exhaustion' or `dysfunction'. This second NFAT-mediated program becomes prominent in CD8+ T cells
exposed to persistent antigen stimulation during chronic viral infections and cancer, and is characterized by a
spectrum of functionally compromised states with decreased cytokine expression and increased expression of
multiple inhibitory receptors (PD-1, CTLA4, LAG3, TIM3, TIGIT). Thus an effective alternative to combination
checkpoint blockade therapies might be to modulate the balance between the NFAT-mediated programs of
activation and exhaustion, and thereby to skew tumor-infiltrating T cells away from exhaustion and towards
effector function. We will test this hypothesis here.
Our experiments with an engineered NFAT1, minimally modified to prevent its interaction with AP1, have
established that the transcriptional program of exhaustion is independent of the NFAT1-AP1 interaction. We
have identified important targets of NFAT in the exhaustion program, including transcription factors of the Nr4a
and Tox families. Moreover, we have shown that Nr4a transcription factors act in exhausted tumor-infiltrating T
cells, in part, by repressing the expression or activation of bZIP transcription factors that would otherwise
promote an effector-like phenotype. In Aim 1, we will identify and characterize the bZIP transcription factors
that are most effective in maintaining the effector function of tumor-infiltrating CD8+ T cells under conditions
that would ordinarily lead to exhaustion; in Aim 2, we will define the differential roles of two NFAT family
members, NFAT1 and NFAT2, in the transcriptional program of exhaustion; and in Aim 3, we will use novel
proteomic strategies to identify NFAT-interacting proteins that cooperate with NFAT to impose the exhaustion
program.
Our proposed studies will te...

## Key facts

- **NIH application ID:** 9974252
- **Project number:** 2R01AI109842-32A1
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Patrick Hogan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $669,740
- **Award type:** 2
- **Project period:** 2014-08-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974252

## Citation

> US National Institutes of Health, RePORTER application 9974252, NFAT, bZIP proteins, and transcriptional programs in lymphocytes (2R01AI109842-32A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9974252. Licensed CC0.

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