# Akt controls alternative splicing in T helper call fate decisions

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $388,425

## Abstract

Abstract
The Serine/Threonine kinase Akt plays a critical role in multiple cellular processes including proliferation,
cell metabolism and survival, through phosphorylation of nuclear and cytoplasmic targets. In CD4 T helper
(Th) differentiation inhibition of Akt and/or mTOR activity results in the induction of T regulatory (Treg) cells,
which are critical for the maintenance of self-tolerance and the prevention of autoimmunity. Treg induction
through exposure of naïve CD4 T cells to low antigen (Ag) doses is negatively correlated with activity of the
Akt/mTOR pathway. The effect of Ag dose on Th differentiation has been shown in several in vivo models
such that low Ag dose favors Treg and Th2 differentiation whereas high Ag doses induces inflammatory
Th1 cells. Our preliminary data show that TCR signals of high vs. low strength result in qualitatively
different Akt phosphorylation, resulting in a change in the substrate specificity of Akt. Quantitative mass
spectrometry analysis of immunoprecipitates (IPs) with an anti-phospho-(Ser/Thr) Akt substrate antibody
revealed multiple differences between Akt substrates phosphorylated in T cells activated with low or high
dose Ag. Intriguingly, we observed that several RNA processing factors are differentially phosphorylated by
Akt depending on Ag dose. In particular, hnRNP L, which regulates the alternative splicing of key
components of the TCR signaling pathway is phosphorylated in T cells stimulated with low, but not high,
dose Ag. This results in Akt-dependent changes in the alternative splicing of TCR signaling components.
These results suggest that different levels of TCR stimulation initiate qualitatively distinct differentiation
programs and that differential regulation of alternative splicing by Akt is one of the key elements
determining Th cell fate decisions. Based on these preliminary findings, we hypothesize Akt-mediated
phosphorylation of RNA processing factors induces the differentiation of naïve Th cells to either
effector or regulatory cells through changes in alternative splicing of TCR signaling components.
Three specific aims are proposed; 1) To determine how TCR signal strength controls Akt activity and
function; 2) To determine the role of Akt phosphorylation in controlling alternative splicing in developing
Teff and Treg cells; and 3) To determine the role of alternative splicing of CD247 in Th cell fate.

## Key facts

- **NIH application ID:** 9825504
- **Project number:** 5R01AI125513-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Penelope Anne Morel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,425
- **Award type:** 5
- **Project period:** 2017-12-20 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9825504

## Citation

> US National Institutes of Health, RePORTER application 9825504, Akt controls alternative splicing in T helper call fate decisions (5R01AI125513-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9825504. Licensed CC0.

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