P110δ

The phosphoinositide 3-kinase (PI3K) p110δ is an enzyme that regulates immune function. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells). Genetic and pharmacological inactivation of p110δ has revealed that this enzymes is important for the function of T cells, B cell, mast cells and neutrophils. Hence, p110δ is consider to be a promising target for drugs that aim to prevent or treat inflammation and autoimmunity and transplant rejection.

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Biochemistry

Like the other class IA PI3Ks, p110δ is a catalytic subunit, whose activity and subcellular localisation are controlled by an associated p85α, p55α, p50α or p85β regulatory subunit. The p55γ regulatory subunit is not thought to be expressed at significant levels in immune cells. These is no evidence for selective association between p110α, p110β or p110δ for any particular regulatory subunit. The class IA regulatory subunits (collectively referred to here as p85) bind to proteins which have been phosphorylated on tyrosines. Tyrosine kinases often operate near the plasma membrane and hence control the recruitment of p110δ to the plasma membrane where it substrate PtdIns(4,5)P2 is found. The conversion of PtdIns(4,5)P2 to PtdIns(3,4,5)P3 triggers signal transduction cascades controlled by PKB (also known as Akt), Tec family kinases, and other proteins that contain PH domains. In immune cells, antigen receptors, cytokine receptors and costimulatory and accessory receptors stimulate tyrosine kinase activity and hence all have the potential to initiate PI3K signalling (refs 1,2).

Functions

For reasons that are not well understood, p110δ appears to be activated in preference to p110α and p110β in a number of immune cells. The following is a brief summary of the role of p110δ in selected leukocyte subsets.

T cells

In T cells, the antigen receptor (TCR) and costimulatory receptors (CD28 and ICOS) are thought to be main receptors responsible for recruiting and activating p110δ. Genetic inactivation of p110δ in mice causes T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete interleukin 2. This may in part results from incomplete assembly of other signalling proteins at the immune synapse. The TCR cannot stimulate the phosphorylation of Akt in that absence of p110δ activity (ref 3).

B cells

p110δ is a key regulator of B cell proliferation and function. p110δ deficient mice have deficient antibody responses. They also lack to B cell subsets: B1 cells (found in body cavities such as the peritoneum) and marginal zone B cells, found in the periphery of spleen follicles) (ref 3).

Mast cells

p110δ controls mast cell release of the granules responsible for allergic reactions. Thus inhibition of p110δ reduces allergic responses (ref 4).

Neutrophils

In conjunction with p110γ, p110δ controls the release of reactive oxygen species in neutrophils (ref 5).

Pharmacology

The US pharmaceutical company ICOS has produced a selective inhibitor of p110δ called IC87114. This inhibitor has been shown to selectively impair B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.

References

1. Okkenhaug, K. and Vanhaesebroeck, B. (2003) PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol 3: 317-330.

2. Deane, J. A. and Fruman, D. A. (2004) Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu. Rev. Immunol. 22: 563-598.

3. Okkenhaug K, et al. (2002) Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297: 1031-4.

4. Ali K et al. (2004) Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature 431:1007-11.

5. Condliffe AM et al (2005) Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood 106:1432-40.