New synthetic molecule prevents autoimmunity without compromising anti-pathogen immunity

In December of 2016 Science Translational Medicine published new study where the authors introduced new, low-molecular weight compound that specifically inhibited autoimmune/allergic responses while sparing anti-pathogen immune response.

This new molecule, AX-024, specifically targets adaptor protein Nck that is involved in low affinity TCR signaling. 

It does not affect signaling delivered via IL-2, BCR or PMA/Ion stimulation.

AX-024 inhibited TLR7/8 agonist, imiquimod (IMQ), induced psoriasis skin symptoms in mice.

Also, AX-024 significantly reduced clinical symptoms associated with mouse model of human multiple sclerosis (MS). Such effect of AX-024 was superior to Fingolimod, a sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing-remitting MS.

Notably, AX-024 in therapeutic dosage did not impair anti-pathogen immunity or memory generation.

In summary, by blocking Nck adaptor protein involved in low-affinity TCR signaling, AX-024 inhibited autoreactivity while preserving necessary capacity for anti-pathogen immunity. Such property makes it desirable candidate for clinical trials in humans.

David Usharauli 

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