Vince, J. | Search bioRxiv

bioRxiv2023

CD45 limits Natural Killer cell development from common lymphoid progenitors

The clinical development of Natural Killer (NK) cell-mediated immunotherapy marks a milestone in the development of new cancer therapies and has gained traction due to the intrinsic ability of the NK cell to target and kill tumour cells. To fully harness the tumour killing ability of NK cells, we need to improve NK cell persistence and overcome suppression of NK cell activation in the tumour microenvironment. The trans-membrane, protein tyrosine phosphatase CD45, regulates NK cell homeostasis, with genetic loss of CD45 in mice resulting in increased numbers of mature NK cells [1-3]. This suggests that CD45-deficient NK cells might display enhanced persistence following adoptive transfer. However, here we demonstrated that adoptive transfer of CD45-deficiency did not enhance NK cell persistence in mice, and instead, the homeostatic disturbance of NK cells in CD45-deficient mice stemmed from a developmental defect in the common lymphoid progenitor population. The enhanced maturation within the CD45-deficient NK cell compartment was intrinsic to the NK cell lineage, and independent of the developmental defect. CD45 is not a conventional immune checkpoint candidate, as systemic loss is detrimental to T and B cell development [4-6], compromising the adaptive immune system. Nonetheless, this study suggests that inhibition of CD45 in progenitor or stem cell populations may improve the yield of in vitro generated NK cells for adoptive therapy.

cell biology↗

bioRxiv2023

Divergent roles for caspase-8 and MLKL in high-fat diet induced obesity and NAFLD in mice

Cell death frequently occurs in the pathogenesis of obesity and non-alcoholic fatty liver disease (NAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill-defined. Here, we show via the direct comparison of mice genetically deficient in apoptotic caspase-8 in myeloid cells, or the essential necroptotic regulators, Receptor-interacting protein kinase-3 (RIPK3) and Mixed lineage kinase domain-like (MLKL), that RIPK3-caspase-8 signaling regulates macrophage inflammatory responses and drives adipose tissue inflammation and NAFLD upon high-fat diet feeding. In contrast, MLKL, divergent to RIPK3, contributes to both obesity and NAFLD in a manner largely independent of inflammation. We also uncover that MLKL regulates the expression of molecules involved in lipid uptake, transport and metabolism and, congruent with this, we discover a shift in the hepatic lipidome upon MLKL deletion. Collectively, these findings highlight MLKL as an attractive therapeutic target to combat the growing obesity pandemic and metabolic disease.

immunology↗