Availability of free cytoplasmic cholesterol augments TCR signaling in CD8 T cells

Few days ago Nature published new research study from mainland China wherein the authors showed that availability of free cholesterol in CD8 T cells augments TCR signaling and contributes to better control of experimental tumor.

This study focus on Acat1 that encodes cholesterol esterification enzymes that convert free cholesterol to cholesteryl esters for storage. The scientists noticed that chemical inhibition of Acat1 in CD8 T cells could augment their cytolytic effector differentiation (granzyme B ↑).

Similar results were obtained with CD8 T cells from Acat1 conditional knockout mice (Acat1^CKO).

Boost of CD8 T cell cytolytic functions with Acat1 inactivation yielded better tumor protection in adoptive transfer experiments as well.

Mechanistically, it appears that availability of excess free cholesterol in Acat1^CKO CD8 T cells improved TCR downstream signaling.

Finally, the authors showed that avasimibe, an Acat inhibitor with a good safety profile in humans, could delay tumor progression in mice and even show synergy with checkpoint inhibitor, anti-PD1 antibody.

In summary, this study suggests that commonly used cholesterol modulating drugs could have important role in CD8 T cells effector function and could influence tumor immunotherapy results.

Here I would like to note that one earlier study showed that reduction of cellular free cholesterol triggered universal STING-cGAS mediated anti-viral type I IFN response. This suggests that on one hand free cholesterol could augment CD8 T cell cytolytic function, but on the other hand it could diminish cell-autonomous anti-viral response.  

David Usharauli

Collapse of cholesterol biosythesis triggers universal anti-viral response

New study in journal Cell may provide mechanistic clue how obesity [and hyper-cholesterolemia] affect immunity. The authors showed that limiting cholesterol biosynthesis automatically triggers universal anti-viral defense state, mimicking natural response to viruses. 

Initially, the authors studied effect of type I IFNs [and its triggers] on lipid metabolism in macrophages. These pilot experiments reveal that de novo synthesis of cholesterol was inhibited by type I IFNs and its triggers, such as virus or PolyI:C. Interestingly, total cholesterol level or its import were not affected.

To decouple direct involvement of host defense response in lipid metabolism, the authors used LysM-Cre-Scap ^fl/fl mice that show limited lipid biosynthesis in myeloid cells. Indeed, Scap^-/- macrophages displayed the same decrease in cholesterol synthesis as type I IFN treated control cells.  

Reduction of cholesterol synthesis in Scap^-/- macrophages was accompanied with increased resistant to viral infection [similar resistance were observed in MKV (mevalonate kinase) and  HMG-CoA reductase deficient cells that have limitation in cholesterol biosynthesis].

This resistance in Scap^-/- macrophages was transferable to control cells via soluble component in conditioned medium (type I IFNs).

Notably, the authors showed that anti-viral resistance in Scap^-/- macrophages could be inhibited by exogenous free cholesterol.

Finally, the authors showed that DNA sensing STING-cGAS pathway was responsible for increased anti-viral state that accompanied collapse of cholesterol synthesis, and here too, free cholesterol supplementation was able to inhibit cGAS activity by its ligand [mechanism is unknown].

In summary, this study raises some of the important questions related to host metabolic shift observed during infections. Inhibition of anti-viral state by free cholesterol could explain diminished immune state observed in obese individuals. In addition, there are studies showing how cholesterol pathways, such as geranylgeranylation could influence TH17 and Foxp3⁺ Treg balance.

David Usharauli