Life Sciences Research for Lifelong Health

Klaus Okkenhaug

Our group focuses on how a group of enzymes called phosphoinositide 3-kinases (PI3Ks) are used by cells of the immune system to instruct and coordinate defences against pathogens. Cells of the immune system can express up to eight different forms of PI3K, which act as second messenger signalling molecules within cells that control diverse of cellular functions and genetic programmes. Our group tries to dissect the unique roles played by individual forms of PI3K with particular focus on their roles in B cells and T cells. We also ask what the effect of inhibiting or enhancing the activity of individual forms of PI3K has on immunity to infections.

Most of our work to date has focused on PI3Kδ. The activation of PI3Kδ is one of the first events that happen inside a T cell or B cell when it first is exposed to a foreign antigen. Because PI3Kδ is expressed at very low levels in other organs in the body, it is thought that targeting PI3K with drugs may be an effective way to suppress immune responses without some of the side effects associated with many immunosuppressive drugs in current use. We therefore work closely with colleagues in pharmaceutical companies who have developed specific inhibitors against PI3Kδ or other forms of PI3K to help predict and understand the effect of such drugs on the immune system.

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Projects in the laboratory

What are the individual roles of each of the class I PI3Ks in lymphocytes?

​Using genetic and pharmacological approaches, we address the functions of individual PI3K isoforms in lymphocytes. At the molecular level, we investigate the basis for their differential engagement by the TCR, BCR and other receptors expressed by lymphocytes. We are especially interested in delineating how p110α and p110δ are differentially activated.

How do PI3Ks regulate immune responses to infection?

Using different models of infection, the effect of inhibiting PI3K on protective immune responses will be investigated. This will involve analysis of both APCs and responding T cells and B cells using pathogens such as Listeria monocytogenes and Streptococcus pneumoniae. The understanding of how PI3Ks control susceptibility to infection is made more pertinent by the discovery that activating mutations in the gene for p110δ are the cause of a primary immunodeficiency disease (APDS).

What is the role of PI3K signalling in regulatory T cells?

We have previously shown that inhibition of p110δ in regulatory T cells (Treg) renders ineffective in preventing T cell-mediated inflammation of the large intestine. More recently we showed that deletion of p110δ in Treg improves immune-mediated rejection of cancer cells. We are currently exploring further consequences of inhibiting PI3K isoforms specifically in Treg and how PI3Ks affect Treg function.
 

Group Members

Latest Publications

The transcription factor BACH2 promotes tumor immunosuppression.

Roychoudhuri R, Eil RL, Clever D

The Journal of clinical investigation
1558-8238: (2016)

PMID: 26731475

Oncogenic PI3Kα promotes multipotency in breast epithelial cells.

Okkenhaug K, Roychoudhuri R

Science signaling
8 1937-9145:pe3 (2015)

PMID: 26535006

PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL).

Okkenhaug K, Burger JA

Current topics in microbiology and immunology
393 0070-217X:123-42 (2016)

PMID: 26350103

Editorial: Lipid Signaling in T Cell Development and Function.

Sauer K, Okkenhaug K

Frontiers in immunology
6 1664-3224:410 (2015)

PMID: 26322043

PI3Kδ Regulates the Magnitude of CD8+ T Cell Responses after Challenge with Listeria monocytogenes.

Pearce VQ, Bouabe H, MacQueen AR

Journal of immunology (Baltimore, Md. : 1950)
1550-6606: (2015)

PMID: 26311905

Cowden's syndrome with immunodeficiency.

Browning MJ, Chandra A, Carbonaro V

Journal of medical genetics
52 1468-6244:856-9 (2015)

PMID: 26246517

PI3K inhibitors in inflammation, autoimmunity and cancer.

Stark AK, Sriskantharajah S, Hessel EM

Current opinion in pharmacology
23 1471-4973:82-91 (2015)

PMID: 26093105