# The role of LAT protein condensation phase transitions in T cell signaling

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $386,274

## Abstract

ABSTRACT - Project 3
A healthy immune system depends on T cells’ abilities to detect foreign agonist pMHC molecules, at near single
molecule levels, among vast numbers of sometimes very similar self-antigens. While the T cell’s fine
discrimination capabilities are experimentally well established, understanding how the molecular machinery of
the TCR signaling system achieves this is far from transparent. Fundamental issues of noise, variation, and
signal fidelity present serious challenges—both for understanding how the T cell works as well as for
development of therapeutic strategies utilizing T cells. Recently, a class of phenomena known as protein
condensation phase transitions have begun to emerge in biology. Originally identified in the context of nuclear
organization and gene expression, a distinct two-dimensional protein condensation on the cell membrane has
now been discovered in the T cell receptor (TCR) signaling system involving the scaffold protein LAT. While the
role of LAT as a scaffold for the clustering of downstream signaling molecules in T cells has long been
recognized, experimental realization that this structure can form through distinct types of phase transition
processes is more recent. Protein condensation phase transitions can exhibit a wide range of properties that
differ substantially from more linear molecular clustering processes, and thus offer a variety of different ways to
regulate the functional output of molecular signaling systems. Project 3 addresses the overarching
hypothesis that unique properties of the LAT protein condensation phase transition enable the
remarkable sensitivity and selectivity T cells exhibit during antigen recognition. We propose a series of
investigations to test aspects of this hypothesis that combine highly quantitative experiments in reconstituted
molecular systems with precision single-molecule live cell experiments in primary T cells. We have preliminary
data indicating that LAT condensation in live T cells is controlled by an unusual type of kinetic phase transition
and that specific molecular features of proximal TCR signaling are tuned to take advantage of this. Confirmation
and elucidation of this discovery will form the foundation of our more detailed investigation into the role of the
phase transition in TCR signaling. While Projects 1 and 2 focus on proximal signaling feedback mechanisms
leading up to LAT phosphorylation and condensate nucleation, and Project 4 examines signaling downstream
from the LAT condensate, Project 3 emphasizes experimental and computational characterization of the LAT
condensation phase transition itself and measurements of how its properties modulate downstream signal
propagation through the following specific aims: 1. Define the factors controlling initiation of LAT
condensation in T cells; 2. Engineer non-condensing LAT and LAT-like systems; 3. Define how LAT
condensates control downstream signaling to Ras and Ca2+ pathways. Insights originating from...

## Key facts

- **NIH application ID:** 10834060
- **Project number:** 5P01AI091580-13
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JAY T. GROVES
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,274
- **Award type:** 5
- **Project period:** 2011-07-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834060

## Citation

> US National Institutes of Health, RePORTER application 10834060, The role of LAT protein condensation phase transitions in T cell signaling (5P01AI091580-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10834060. Licensed CC0.

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