Discovery reveals a regulatory role for the adaptive immune system

Researchers led by Kebin Liu, PhD, in collaboration with colleagues including other members of the GRU Cancer Center, Drs. McGaha, Zhou, and Mellor, have demonstrated for the first time a novel mechanism through which the adaptive immune system regulates differentiation of the innate immune system’s myeloid cells.

The immune system is highly complicated, intricately orchestrated, and critical for protecting the body from pathogens and other invaders such as cancer cells. It normally operates via a two-tiered approach, with the innate immune components (cells of the myeloid lineage) surveying the body for foreign constituents it recognizes and activating the adaptive immune components (T cells and B cells) to subsequently respond to invaders that escape its repertoire. Diseases, including cancer, can result from deficiencies in these processes.

For example, in leukemia and other cancers, myeloid cells – called MDSCs, characterized by factors such as CD11b+Gr1+ in mice and CD11b+CD33+ in humans – fail to differentiate and instead accumulate in an immature form, unable to properly function.
In the current study, Dr. Liu’s team studied myeloid differentiation in vivo, recognizing IRF8 as an essential transcription factor for this process. Whereas myeloid differentiation was deregulated in IRF8 knockout (IRF8 KO) mice (resulting in MDSC accumulation), differentiation surprisingly remained intact when the IRF8 deficiency was limited to myeloid cells (IRF8 MKO). Although the IRF8 MKO model exhibited decreased spontaneous apoptosis, presumably due to decreased IRF8-regulated apoptosis genes, this did not affect MDSC accumulation. Limiting the IRF8 deficiency to T cells alone (IRF8 TKO), however, was sufficient to generate the MDSC accumulation seen in IRF8 KO mice, indicating the role of T cell IRF8 expression in myeloid differentiation.
The study further identified an inverse relationship between the expression of IRF8 and the cytokine GM-CSF in T cells. The researchers concluded that IRF8 functions both intrinsically – in myeloid cells, to regulate myeloid cell turnover – and extrinsically – in T cells, to regulate myeloid cell differentiation, though repressed GM-CSF expression.