# Regulation of T cell responses through Zap70 and TCR interaction dynamics.

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $436,500

## Abstract

ABSTRACT
The immune system's ability to adjust the potency of its response to an external threat is exploited by most
immunotherapies. Extremely successful examples are the checkpoint therapies that target the inhibitory
receptors PD1 or CTLA4 to treat cancer. These immunotherapies cure some patients, but successful
outcomes are still limited. Like most immunotherapies, checkpoint therapies target pathways that affect the
amplitude and duration of existing immune response, but do not target the pathways that actually induce
immune responses, e.g. the antigen receptor pathways in T and B cells. One reason for this is that appropriate
immune responses have to stay within the narrow window between autoimmunity and immunodeficiency.
Traditional treatments that block or activate cell surface receptor or enzymes are to crude and therefore
frequently cause immunodeficiency or immune responses that cause detrimental side effects, such as cytokine
storms and autoimmunity. Targeting antigen receptors directly requires a fine adjustment of activation
thresholds, signaling amplitudes and durations. Recent findings suggest that the assembly kinetics of signaling
molecules and their distribution within nanometer sized plasma membrane domains control T cell receptor
(TCR) signal transduction. Targeting these mechanisms would change the probabilities of particular signaling
events to occur while maintaining antigen specificity and inherent feedback mechanism. Therapies based on
these principles might only slightly change T cell activation thresholds, strength and duration and result in
additional or less immune responses without the detrimental side effects. The proposed research uses a
combination of biochemical, structural and cutting-edge microscopy approaches to elucidate the molecular
underpinnings that control the assembly dynamics and plasma membrane distribution of signaling molecules in
the TCR signaling cascade. The studies will provide a comprehensive understanding of the mechanism that
control the release of Zap70 kinase from the TCR into the plane of the plasma membrane to amplify and
disperse antigenic stimuli. Single molecule imaging will show the first example of a kinase (i.e. Zap70) that is
recruited to a receptor without intrinsic catalytic activity (i.e. the TCR) and released to encounter its substrates
in spatially distinct membrane domains. Most importantly, the potential of changing T cell responses against
tumor or self-antigens by modulating Zap70 conformations and thereby its interaction kinetics with the TCR will
be tested in animal models for melanoma and diabetes.

## Key facts

- **NIH application ID:** 9852455
- **Project number:** 5R01GM118879-03
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Bjoern F Lillemeier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,500
- **Award type:** 5
- **Project period:** 2018-02-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852455

## Citation

> US National Institutes of Health, RePORTER application 9852455, Regulation of T cell responses through Zap70 and TCR interaction dynamics. (5R01GM118879-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852455. Licensed CC0.

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