Klaus Okkenhaug

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The role of PI3Ks in T cell immunity

T cells help to orchestrate immune responses to rid the body of disease-causing agents such as viruses, bacteria and parasites. T cells have evolved to distinguish self (any cell in the body) from non-self (potential infectious agents). T cells can recall a previous encounter with a particular invader (pathogen) and mount a faster and more vigorous response to subsequent encounters to the extent that the infection goes unnoticed. This is how resistance to particular strains of the flu develops and is also how vaccines have their protective effect.

When a cell has been infected with or has ‘engulfed’ (eaten) a pathogen, peptide fragments (antigens) are displayed on the cell surface to alert the immune system to the presence of an invader. T cells recognise these peptides via the T cell receptor (TcR). However, recognition of a peptide from the foreign invader is in itself insufficient to initiate most immune responses. Specialised cells called antigen presenting cells (APCs) that have been exposed to the pathogen also express a protein called B7 on the cell surface – this alerts the immune system by sending a second signal through a protein CD28 located in the membrane of the T cell.

CD28 and the TcR play a critical role in alerting the immune system; they activate phosphoinositide 3-kinases (PI3Ks), a family of enzymes used by B and T cells to generate signalling molecules which influence cell division, differentiation, cell survival, metabolism, motility and gene expression. We are investigating the regulation of PI3Ks in T cells using genetic approaches in conjunction with fluorescence-based technologies to monitor signalling pathways. We also investigate how genetic manipulation of PI3K signalling influences different kinds of immune responses. Results from these investigations may provide rationale for the use of PI3K inhibitors in therapeutic settings.

Sometimes T cells mistakenly recognise components of the different cells and organs in the body as infectious agents, leading to autoimmune diseases like rheumatoid arthritis, multiple sclerosis, juvenile diabetes, systemic lupus erythematosus and other devastating illnesses. Much scientific research effort is therefore directed towards the goal of developing drugs that can suppress the immune system under circumstances where it is too active or where it turns against self rather than infectious agents. One approach is to interfere with the chemical signals that are generated inside the T cells upon recognition of foreign agents (or self, as the case may be).