Life Sciences Research for Lifelong Health

Klaus Okkenhaug

Klaus Okkenhaug is now Professor of Immunology at the University of Cambridge. Visit his page there for full details of his current research.

Research Summary

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.

Latest Publications

Targeting PI3Kδ Function For Amelioration of Murine Chronic Graft-Versus-Host Disease.
Paz K, Flynn R, Du J, Tannheimer S, Johnson AJ, Dong S, Stark AK, Okkenhaug K, Panoskaltsis-Mortari A, Sage PT, Sharpe AH, Luznik L, Ritz J, Soiffer RJ, Cutler CS, Koreth J, Antin JH, Miklos DB, MacDonald KP, Hill GR, Maillard I, Serody JS, Murphy WJ, Munn DH, Feser C, Zaiken M, Vanhaesebroeck B, Turka LA, Byrd JC, Blazar BR

Chronic graft-versus-host disease is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T-cells can differentiate into pathogenic T helper (Th)-17 cells and germinal center -promoting Tfollicular helper cells, resulting in cGVHD. Phosphoinositide-3-kinase-δ, a lipid kinase, is critical for activated T-cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T-cells that become Tfhs is required for cGVHD in a non-sclerodermatous multi-organ system disease model that includes bronchiolitis obliterans, dependent upon GC B-cells, Tfhs, and counterbalanced by Tfollicular regulatory cells, each requiring PI3Kδ signaling for function and survival. Although B-cells rely on PI3Kδ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3Kδ kinase-dead mutant donor bone marrow derived GC B-cells still supported BO cGVHD generation. A PI3Kδ-specific inhibitor, compound GS-649443 that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1-dependent and Th17-associated scleroderma model, GS-649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of FDA-approved PI3Kδ inhibitors for cGVHD therapy in patients. This article is protected by copyright. All rights reserved.

+ View Abstract

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, , 1600-6143, , 2019

PMID: 30748099

The PI3K p110δ Isoform Inhibitor Idelalisib Preferentially Inhibits Human Regulatory T Cell Function.
Chellappa S, Kushekhar K, Munthe LA, Tjønnfjord GE, Aandahl EM, Okkenhaug K, Taskén K

In chronic lymphocytic leukemia (CLL), signaling through several prosurvival B cell surface receptors activates the PI3K signaling pathway. Idelalisib is a highly selective PI3K (PI3Kδ) isoform-specific inhibitor effective in relapsed/refractory CLL and follicular lymphoma. However, severe autoimmune adverse effects in association with the use of idelalisib in the treatment of CLL, particularly as a first-line therapy, gave indications that idelalisib may preferentially target the suppressive function of regulatory T cells (Tregs). On this background, we examined the effect of idelalisib on the function of human Tregs ex vivo with respect to proliferation, TCR signaling, phenotype, and suppressive function. Our results show that human Tregs are highly susceptible to PI3Kδ inactivation using idelalisib compared with CD4 and CD8 effector T cells (Teffs) as evident from effects on anti-CD3/CD28/CD2-induced proliferation (order of susceptibility [IC]: Treg [.5 μM] > CD4 Teff [2.0 μM] > CD8 Teff [6.5 μM]) and acting at the level of AKT and NF-κB phosphorylation. Moreover, idelalisib treatment of Tregs altered their phenotype and reduced their suppressive function against CD4 and CD8 Teffs. Phenotyping Tregs from CLL patients treated with idelalisib supported our in vitro findings. Collectively, our data show that human Tregs are more dependent on PI3Kδ-mediated signaling compared with CD4 and CD8 Teffs. This Treg-preferential effect could explain why idelalisib produces adverse autoimmune effects by breaking Treg-mediated tolerance. However, balancing effects on Treg sensitivity versus CD8 Teff insensitivity to idelalisib could still potentially be exploited to enhance inherent antitumor immune responses in patients.

+ View Abstract

Journal of immunology (Baltimore, Md. : 1950), , 1550-6606, , 2019

PMID: 30692213

PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.
Stark AK, Chandra A, Chakraborty K, Alam R, Carbonaro V, Clark J, Sriskantharajah S, Bradley G, Richter AG, Banham-Hall E, Clatworthy MR, Nejentsev S, Hamblin JN, Hessel EM, Condliffe AM, Okkenhaug K

Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19B220 B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target.

+ View Abstract

Nature communications, 9, 2041-1723, 3174, 2018

PMID: 30093657

Group Members

Latest Publications

Targeting PI3Kδ Function For Amelioration of Murine Chronic Graft-Versus-Host Disease.

Paz K, Flynn R, Du J

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
1600-6143: (2019)

PMID: 30748099

The PI3K p110δ Isoform Inhibitor Idelalisib Preferentially Inhibits Human Regulatory T Cell Function.

Chellappa S, Kushekhar K, Munthe LA

Journal of immunology (Baltimore, Md. : 1950)
1550-6606: (2019)

PMID: 30692213

PI3K induces B-cell development and regulates B cell identity.

Abdelrasoul H, Werner M, Setz CS

Scientific reports
8 2045-2322:1327 (2018)

PMID: 29358580

Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis.

Kishore M, Cheung KCP, Fu H

Immunity
47 1097-4180:875-889.e10 (2017)

PMID: 29166588

Multi-tissue DNA methylation age predictor in mouse.

Stubbs TM, Bonder MJ, Stark AK

Genome biology
18 1474-760X:68 (2017)

PMID: 28399939

Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy.

Okkenhaug K, Graupera M, Vanhaesebroeck B

Cancer discovery
2159-8290: (2016)

PMID: 27655435

Ionic immune suppression within the tumour microenvironment limits T cell effector function.

Eil R, Vodnala SK, Clever D

Nature
537 1476-4687:539-543 (2016)

PMID: 27626381