31 Jan 2020

Blood cell life cycle further unravelled

Professor David Tarlinton (right) with some
of his group in 2016, shortly after the move
to Monash University
by Anne Crawford

A study into a transcription factor important in blood cell development and longevity took the Department of Immunology and Pathology's Professor David Tarlinton and collaborators on a circuitous route to findings that revealed that the factor is far more complex than was first thought.

IRF4 (interferon regulatory factor 4) is critical for the development, maintenance, and function of blood cells. It regulates the transcription of genes that specify the production of plasma cells – the body’s antibody-producing cells – and is crucial for the immune system’s B cells to become activated in response to antigens and to ultimately become plasma cells.

IRF4 is of interest therapeutically not only for its role in maintaining normal immune function but also because it has been shown to affect several autoimmune diseases and cancers.

A recent paper in Cell Reports led by Professor Tarlinton in collaboration with researchers at the Walter and Eliza Hall Institute arrived at some unexpected findings about the protein.

The researchers initially hypothesised that IRF4 controlled the expression of the pro-survival gene MCL1. MCL1 (myeloid cell leukaemia-1) is frequently elevated in human cancer cells, keeping them alive. This is particularly so in the cancers of plasma cells themselves – multiple myeloma – which have a very poor prognosis.

“We thought that since IRF4 continues to be expressed in antibody-secreting cells and has some critical function in those cells – not just in their formation but also in their continued survival – that this could be through MCL1,” Professor Tarlinton said.

But the findings, like so many in scientific endeavour, weren’t linear.

“We thought that one and one would equal two but it equalled about 100!” Professor Tarlinton said.

The researchers deleted IRF4 from plasma cells, replacing it with another pro-survival gene to look at the consequences of cell behaviour without it.

“Lots of genes changed; some upregulated, some down. When we tried to group them according to what they were known to control they fell into a whole number of processes, most of those metabolic,” Professor Tarlinton said.

But the effect on cell metabolism of deleting the gene wasn’t clear-cut either; while the researchers expected metabolism in the plasma cells to be poor after IRF4 was removed, it was inexplicably higher than normal. They then posited that the overactive metabolism was causing the death of cells but was unable to block this with known inhibitors.

“This showed us that what IRF4 does is to regulate a lot of processes that are necessary for the survival and function of these cells,” Professor Tarlinton said.

“Rather than controlling a very specific pathway between the surface of the cell and the signalling it receives from outside into the single, cell survival gene (MCL1) – our starting model – IRF4 actually is sitting at the apex of regulating global cell behaviour in antibody-secreting cells,” he said.

“It controls a lot of genes and they presumably are responsible for controlling metabolism so the cell stays within a normal range.”

Cells that ‘sense’ they are not behaving normally kill themselves, a process called apoptosis. “The loss of IRF4 leads to a sense of a kind of ‘inappropriate’ behaviour; the cells then do in fact die.

“Plasma cells are quick to die outside their correct environment.”

The study found that deleting IRF4 had no measurable impact on the amount of MCL1 protein in either mouse or human plasma cell lines. Therefore, while IRF4 was necessary for plasma cell survival, and this was due at least in part to inhibiting apoptosis, it did not mediate this effect by regulating MCL1.

“It was confusing but very educational!” Professor Tarlinton said.

“We still don’t know the factors that control this unique survival gene (MCL1) but we’ve eliminated some of the candidates,” he said.

The study did, however, deepen understanding of how plasma cells are engineered and were ‘wired’ to function, he said. “They basically divide up their activities into regulatory blocks – IRF4 controls one of these blocks.”

Professor Tarlinton and colleagues at the Walter and Eliza Hall Institute including long-term collaborator and author on this paper Professor Stephen Nutt, previously made landmark findings into MCL1 before Professor Tarlinton came to Monash University to head the Department of Immunology and Pathology in 2016. Also instrumental in this study were first author haematologist Dr Michael Low and post-doctoral fellow Dr Erica Brodie.

To read the paper – https://www.ncbi.nlm.nih.gov/pubmed/31775034

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