Foxp3+ Tregs depletion activates anti-cancer immunity via eosinophils

Eosinophils are usually associated with atopic/allergic conditions. However, as with all cells involved in type II immune response, eosinophil's role in host's defense is not entirely clear.

This new paper in Nature Immunology provided evidence for eosinophil's anti-tumor function. The paper itself is quite "primitive", observation-type of research article. It belongs more to JEM, if you ask me. Still, it was accepted within 1 month of its submission to Nature Immunology. 

It appears that initial focus of this research was Foxp3+ Tregs. The authors showed that Foxp3⁺ Tregs depletion in Foxp3.LuciDTR-4 mice induced B16 melanoma rejection expressing nominal OVA antigen (MO4 tumor cells).

Surprisingly, this rejection of MO4 tumor was accompanied with selective eosinophil infiltration at tumor site.

Indeed, concomitant depletion of eosinphils with Siglec-F antibody significantly reduced anti-cancer effect seen with Foxp3⁺ Tregs depletion.

Additional experiments showed that anti-tumor effectiveness of adoptively transferred OVA-specific CD8 T cells were eosinophil dependent, though only in vitro IFN-γ + TNF-α activated, but not resting eosinophils could provide such help to CD8 T cells. Eosinophils alone were not effective.

The authors went on to show that activated eosinophils attracted CD8 T cells to tumor site and promoted normalization of tumor vasculature.

In summary, these results suggests that depletion of Foxp3⁺ Tregs activates eosinophils which in turn recruit CD8 T cells into tumor site leading to anti-tumor effect.

Now, why are eosinophils specifically involved in tumor protection in this model is not clear. What attracts eosinophils into tumors?

David Usharauli

CD8 T effector cells monitor liver tissue with the help of platelet scouts

Liver is a body's chemical detox factory. Several viruses including HBV can infect liver cells called hepatocytes. What is interesting about HBV that it is essentially a non-cytopathic virus in immunocompetent hosts, meaning that it can infect hepatocytes and does no "damage" to it (unlike, for example, influenza virus infection of airway epithelial cells). More likely, due to continuing immunosurveillance of liver tissue by innate immune cells, like NKT and NK cells, liver cells showing obvious abnormalities are quickly eliminated.

But what about adaptive immune system? New study in journal Cell explains how CD8 T_E cells monitor liver for the presence of viral antigens. It appears that CD8 T_E are using platelets for docking on liver endothelial cells to initiate surveillance.

The authors showed that contrary to conventional thinking, initial docking of CD8 T_E cells on liver endothelial cells was antigen-independent in HBV infected hosts.

Next, the authors showed that this particular docking of CD8 T_E cells on liver endothelial cells was independent of known mechanisms involving integrins, selectins or chemokines.

Unexpectedly, initial docking of CD8 T_E cells on liver endothelial cells was reduced by platelet depletion or when adoptively transferred platelets lacked CD44 expression (CD44 interacts with hyaluronan).

The authors showed that after initial Ag-independent docking of CD8 T_E cells on liver endothelial cells via platelets, CD8 T_E cells subsequent liver tissue monitoring and effector function (crawling cessation and IFN-γ secretion) was Ag-dependent events.

In summary, this study described novel mechanism of cell-cell cooperation between CD8 T_E cells and platelets. It is not clear what signals promotes adhesion of CD8 T_E cells to platelets. It is not even clear why platelets are adhering to liver sinusoidal endothelial cells in the first place. Are platelets sensing subtle changes in liver tissue due to non-cytopathic HBV infection?

David Usharauli