Singapore - Immunology: Lose some, gain some

Calicneurin inhibitors, used clinically as immunosuppressive drugs, are shown to confer a growth advantage to myeloid cells

Cyclosporin A is a calicneurin inhibitor used for suppressing the immune system during organ transplantation and in the treatment of autoimmune diseases. It works by inhibiting a family of transcription factors called NFATs, which are important for T-cell development and function. However, NFATs’ effects on other cell types involved in the innate immune response had not yet been elucidated.

Jan Fric at the A*STAR Singapore Immunology Network and co-workers1 have now shown that in addition to promoting T-cell development, NFATs also suppress the maturation of myeloid cells. Myeloid cells provide the body’s first line of immune defence, as it is their job to detect and eliminate pathogens. These findings have implications for how calicneurin inhibitors should be used clinically in the future.

As their model system, Fric and co-workers used mice that had been irradiated to remove all of their immune cells. Into these mice they injected hematopoietic stem cells, which can mature along one of two paths; they can become either myeloid cells or lymphoid cells such as T cells. The mice got a mixture of normal control stem cells and stem cells that had been genetically engineered to express an inhibitor of NFAT signalling. Each of these cell types had different molecular tags so the researchers could trace their distinct lineages.

Eight weeks later, the researchers found that cells with the NFAT inhibitor preferentially expanded into myeloid cells, whereas the normal control cells expanded into both myeloid and lymphoid cells in the expected ratios. There was not enough NFAT inhibitor to completely abolish T-cell development; rather, the NFAT inhibitor actively promoted development along the myeloid pathway.

These results were reconstituted in in vitro systems, whereby Fric and co-workers determined that NFAT negatively regulates myeloid expansion by suppressing the transcription of essential cell cycle genes. Inhibiting NFAT relieves this suppression and allows myeloid cells to progress more rapidly through the cell cycle, resulting in an expansion of the myeloid cell population.

“Calcineurin inhibitors are clinically used primarily to inhibit T-cell functions during transplantations or other immune disorders,” noted Fric. “Unfortunately, such a treatment can cause a higher susceptibility to infections and other side effects, due to the suppression of the immune system. Here we showed for the first time that myeloid cells can also be a target of these inhibitors. Our findings can help to better understand the drug’s side effects, and eventually, long term further research can lead to therapy modifications.”

Fric thanked his A*STAR co-worker Paola Castagnoli for her support in this study. “NFAT signaling in dendritic cells has been a long-time interest of Paola Castagnoli's group, where this research was performed," says Fric.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network

References

1. Fric, J. et al. Calcineurin/NFAT signaling inhibits myeloid haematopoiesis. EMBO Molecular Medicine 4, 269–282 (2012). | article