# Critical Role for KLF2 in Regulation of PD-1 Expression in T cells

> **NIH NIH R03** · NORTHWESTERN UNIVERSITY · 2021 · $79,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Numerous transcription factors which control the differentiation, function, migration and survival of different
classes of effector and memory T cells have been identified, but the precise functions of many of these
transcription factors which regulate the outcome of an immune response are incompletely defined. KLF2, a
member of the Kruppel-like factor family, has diverse roles in the immune system, and in particular plays a
critical role in controlling migration of T (and B) cells via its control of expression of key homing receptors
which determine selective trafficking capabilities. Other functions of KLF2 remain mostly undefined. A
striking and unusual feature of KLF2 is its rapid loss of expression in T, B and multiple other cell types
following cellular activation. Despite this feature of KLF2 being known for over two decades and efforts by
several investigators, the physiologic importance of this loss of KLF2 remains poorly defined. We have
generated a novel, powerful, and sophisticated mouse model which for the first time makes possible
interrogation of the functions of KLF2 downregulation. In this model, loss of KLF2 expression is completely
and permanently blocked in any cell type which expresses or which once expressed cre recombinase. We
present extensive data showing that this novel mouse model has a normal peripheral T cell compartment
prior to immunologic challenge, yet induction of CD8 T cell effectors in response to infection with LCMV
Armstrong is sharply impaired. In addition, we unexpectedly found that expression of PD-1, a major inhibitory
receptor which is an important marker of exhausted T cells and the primary target of checkpoint blockade
therapy, is higher and far more sustained in CD8 T cells which cannot turn off KLF2 expression, compared to
WT, despite the well established fact that LCMV Armstrong causes acute resolving infection and does not
induce T cell exhaustion. We propose to explore the regulation and function of PD-1 in this novel mouse
model. In Aim 1, we will determine the role of PD-1 signaling in defective responses of K121R CD8 T cells.
In Aim 2, we will determine whether KLF2 maintains PD-1 expression via repression of Blimp-1. These
studies will significantly advance our understanding of the functions of KLF2 and KLF2 downregulation in T
cell responses.

## Key facts

- **NIH application ID:** 10193685
- **Project number:** 1R03AI159591-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Geoffrey S. Kansas
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $79,500
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10193685

## Citation

> US National Institutes of Health, RePORTER application 10193685, Critical Role for KLF2 in Regulation of PD-1 Expression in T cells (1R03AI159591-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10193685. Licensed CC0.

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