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Department of Pathology

 

Natural killer (NK) cells are critical to immune surveillance against infections and cancer.

Their role in immune surveillance requires that NK cells reside within tissues in a quiescent state. The mechanisms by which NK cells remain quiescent in tissues are incompletely understood.

 

The transcriptional repressor BACH2 plays a critical role within the adaptive immune system and promotes the quiescence of multiple adaptive immune lineages. However, its function within innate lymphocytes, including NK cells, has been unclear. By studying mice with systemic or NK cell-restricted conditional deletion of BACH2, Charlotte Imianowski and others in the Roychoudhuri group showed that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function.

 

Genome-wide transcriptional analyses showed that BACH2 regulates the gene expression programme of NK cell maturation. Loss of BACH2 expression within NK cells resulted in an accumulation of activated NK cells with unrestrained cytotoxic function within tissues, which mediated augmented immune surveillance to pulmonary cancer metastasis.

 

The researchers also found that BACH2 regulates a somewhat shared transcriptional programme in NK cells and CD8+ T cells, revealing a fundamental molecular analogy between the differentiation programmes of these two cytotoxic lymphoid lineages.

 

The work represented an international collaboration between the Roychoudhuri, Halim and Okkenhaug groups within Cambridge and the Kurosaki (Japan) and Sun (US) groups. The findings define a critical role of BACH2 as a negative regulator of NK cell quiescence and suggest that factors which regulate the maturation state of NK cells in tissues control anti-metastatic immunity.

 

It is hoped that these new insights will pave the way for a better understanding of how tissue immunity to metastasis is regulated and for the development of new ways to augment such immunity for the treatment of cancer patients.

 

Read the paper BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis published in the Journal of Experimental Medicine here: https://doi.org/10.1084/jem.20211476 

 

Find out more about the Roychoudhuri group here.

 

 


 

About the Authors

 

 

Dr Charlotte Imianowski 

Charlotte graduated in 2016 from the University of Oxford with a BA in Cell and Systems Biology, with a focus on Immunology. After working as a Research Assistant at the Dunn School of Pathology at the University of Oxford, she joined Rahul Roychoudhuri’s group as a PhD student in 2017. Charlotte graduated with a PhD from the Department of Pathology, the University of Cambridge, in 2022. Her Doctoral research focused on transcriptional regulation of NK cell maturation and function. Her work revealed that the transcription factor BACH2, previously shown to be important for the regulation of adaptive lymphocytes, also functions in NK cells to repress their maturation and that this has implications for anti-tumour immunity.  Charlotte is now working as a postdoctoral scientist in the group, investigating immunotherapeutic approaches to cancer. 

Find out more about Charlotte here.

Keep up with Charlotte on Twitter @CImianowski

 

 

 

Dr Rahul Roychoudhuri

Rahul Roychoudhuri is an Associate Professor at the University of Cambridge Department of Pathology and Director of Studies in Pathology at St Catherine’s College. He is the Theme Lead in Infection and Immunity at the School of the Biological Sciences.

Find out more about Rahul here. 

Keep up with Rahul on Twitter @RoychoudhuriLab