# Cyclin-dependent kinases: Novel switches in anergy and targets for tolerance

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $420,000

## Abstract

DESCRIPTION (provided by applicant): The proliferation of a few, antigen-reactive lymphocytes into a large population of effector cells is a fundamental property of adaptive immunity. The cell division that fuels this process is driven by signals from antigen, costimulatory and growth factor receptors, and is controlled by the cyclin-dependent kinase (CDK) cascade. Our work during the last two funding periods has focused on the role of cyclin-dependent kinases in T cell differentiation, anergy and tolerance. Our work established critical roles for CDK2 and its inhibitor p27kip1 in controlling the balance between immunity and tolerance. We showed that mice with a germline deletion of CDK2 accept cardiac allografts under conditions that lead to rejection in wild-type recipients, while mice lacking p27kip1 are highly resistant to tolerance induced by costimulatory blockade. Surprisingly, these factors do not operate through regulation of T cell cycle progression. Instead, we found that CDK2 activity promotes T helper differentiation, and that CDK2-deficient Treg exhibit a gain of suppressive activity. In this renewal application, we will explore this exciting new role for the CDK2 pathway in the control of regulatory T cell function, focused mainly by our findings that Foxp3 is phosphorylated and targeted for degradation by CDK2, and that dysregulated CDK2 activity opposes the induction and stability of Foxp3+ Treg. The proposed work will forward our basic understanding of how Foxp3 and regulatory T cell function is regulated, and will also have important therapeutic implications. Small molecule CDK antagonists are currently in phase I clinical trials, and based on our findings, could potentially be used to promote regulatory T cell function and tolerance in autoimmune and organ transplant patients.

## Key facts

- **NIH application ID:** 9828732
- **Project number:** 5R01AI054643-15
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** ANDREW D WELLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,000
- **Award type:** 5
- **Project period:** 2002-07-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828732

## Citation

> US National Institutes of Health, RePORTER application 9828732, Cyclin-dependent kinases: Novel switches in anergy and targets for tolerance (5R01AI054643-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9828732. Licensed CC0.

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