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Department of Pathology

 

A new publication sets out to figure out what makes T cells stick

Many genetic and biochemical pathways are highly conserved in all living organisms.

 

One such pathway is the so-called PI3K pathway, an ancient nutrient-sensing pathway found in worms, flies and humans.

 

Its simplest manifestation involves three protein components: PI3K, AKT and FOXO, and a lipid called PIP3.

 

PI3K generates PIP3 which activates AKT. AKT then turns the transcription factor FOXO off, releasing cells to perform a variety of functions (FOXO keeps cells in a quiescent, low-metabolic state).

 

In mammals in general and immune cells in particular, we now know of hundreds of proteins in addition to AKT that can bind PIP3. We only know the function of a few of these – what about all the rest?

 

Kristoffer Johansen, a PhD student who split his time between Pam Schwartzberg’s lab at the NIH and Klaus Okkenhaug’s lab in Cambridge, determined which of these might be important for T cell function.

 

T cells patrol the body seeking infectious pathogens and orchestrate the immune response against these.

 

In doing so, they adhere to other cells, either so they can move out of the blood vessels and into lymph nodes or other tissues, or alternatively, they can communicate more effectively with other immune cells.

 

To do so, they activate a protein called LFA1 on the cell surface. We already knew PI3K could regulate LFA1 and that this did not involve AKT.

 

Hence, Kristoffer set out to find out what linked PI3K to LFA1. To explore this, he set up a genetic screen (using CRISPR/Cas9 technology) to target all known and suspected PIP3 binding proteins (more than 500 in total).

 

One protein called was found to inhibit LFA1 such that when the expression of RASA3 was ablated, the T cells stuck to other cells longer than they normally would.

 

This led to impaired immune responses as the T cells were less capable of moving freely between the blood, lymph nodes and other tissues.

 

Additional experiments showed that PI3K and PIP3 turn RASA3 off, thereby leading to the full activation of LFA1.

 

This study demonstrates that there is much more to PI3K than the canonical PI3K-AKT-FOXO axis and that PI3K plays a critical role in the trafficking of T cells in and out of blood vessels.

 

This new knowledge helps us better understand how drugs that target PI3Ks impact the immune system in autoimmune diseases and cancer.

 

 

 


 

The published article A CRISPR screen targeting PI3K effectors identifies RASA3 as a negative regulator of LFA-1–mediated adhesion in T cells can be found here: https://www.science.org/doi/10.1126/scisignal.abl9169 

 

Science Editor's Summary: Unsticking T cells

T cells must adhere to and release from other cells to migrate into tissues and stimulate antibody production. The integrin LFA-1 promotes T cell adhesion, and activation of LFA-1 requires PI3K, a kinase that generates the lipid second messenger PIP3. Johansen et al. revealed the GTPase-activating protein RASA3 as an inhibitor of LFA-1 in a screen designed to identify PIP3-binding proteins whose deficiency altered the ability of T cells to bind to an LFA-1 ligand. Due to an increase in adhesion, T cells lacking RASA3 were impaired in entering or exiting lymph nodes and mice with RASA3-deficient T cells had defective responses to immunization. Thus, RASA3 is critical for terminating the LFA-1-dependent adhesion of T cells to enable migration and other T cell functions.

 

 


 

 

Dr Kristoffer Haurum Johansen

Kristoffer is a Postdoc in the Department of Health Technology Experimental & Translational Immunology T-Cells and Cancer at the Technical University of Denmark.

Previously he completed his PhD at the University of Cambridge in the Immunology Division with Professor Klaus Okkenhaug and the NIH studying T cell signalling/LFA1 activation. 

You can keep up with Kristoffer on Twitter @KrisHaurum

 

 

 

 

 

Professor Klaus Okkenhaug

Klaus is Professor of Immunology and Head of the Division of Immunology at the Department of Pathology at the University of Cambridge. His group investigates the role of cell signalling pathways in the immune system, with particular focus on the Phosphoinositide 3-kinases (PI3Ks). In recent years, he has contributed to the description of a new primary immunodeficiency syndrome caused by activated PI3Kδ mutations (APDS) and his group demonstrated that deletion of PI3Kδ in regulatory T cells unleashes a potent anti-tumour response. He has published more than 100 articles and reviews in leading journals and is an internationally-leading authority on the role of PI3Ks in immunity, infection and cancer.

You can keep up with him and his research on Twitter @KlausOkken

 

 

 

 

Pamela L. Schwartzberg

Pamela is Chief of the Cell Signaling and Immunity Section at the National Institute of Allergies and Infectious Diseases. 

Her research focuses on Signal transduction in T lymphocytes, Genetic, cellular, biochemical, and genomic analyses of T-cell function in the context of immunization, cancer, and responses to infectious diseases. She is also interested in the study of lymphocytes from patients and models of genetic primary immunodeficiencies. 

Find out more about Pamela and her work here>

 

 

 

 

 

 

 

 

 

 


 

This article was submitted by Professor Klaus Okkenhaug.

Image Credit:  Julie Hagedorn-Thomsen