**4. Final considerations**

In mouse model, treatment with G-CSF generates in the HSCT donors an increase of Treg cells, which may be responsible for the generation of suppressor neutrophils. When transferred to the HSCT receptors, these neutrophils are able to suppress the GVHD by reducing the clinical and histopathological signs of the disease. On the other hand, these protected individuals retain the anti-leukemia effect, which is important to prevent relapses, and reject allogeneic skin grafts, showing that the protection of GVHD is due to a specific suppression and not a systemic immunosuppression of the recipient, which claims for a T cell function.

The type of neutrophil generated after G-CSF treatment is obviously different from the classical neutrophil, known as inflammatory. Although activated and mature, they express low levels of MHC-II and co-stimulatory molecules, low levels of MPO, and are degranulated. On the other hand, they are producers of the suppressive cytokine IL-10 and also show an increase in IL-4 and IL-22. Together, these characteristics make this cell a potential suppressor, since several mechanisms able to modulate T cells are present.

We believe that after transfer to the recipient, these neutrophils (which have a longer half-life, as recently reported in the literature) rapidly colonize the sites activated by the conditioning regimen. It is known that in 3 days there is neutrophil colonization in mLN. Although reports in the literature associate this early neutrophil colonization with the increased damage caused by GVHD, this neutrophil is of a distinct subtype, generated after treatment with G-CSF. Thus, in these activated sites, neutrophils can act to control local inflammation, generating a regulatory environment, favoring the generation of new Treg cells that amplify the specific protection observed in our study.

We conclude that neutrophils function goes beyond the microbicidal function. The classical view is too narrow to explain the many features acquired by these cells. Many different and complex subtypes of regulatory neutrophils have been recently described. Although their characterization is not precise, regulatory neutrophils can be grouped together based on their functional profile. Also, the interaction between these neutrophils and other cell types, such as the ones described here (macrophages, NK, NKT, ILC, DC, B and T cells), potentiate the regulatory response in different conditions. So, the regulatory neutrophils confer an important bridge between innate and adaptive immune system in many different conditions, building a new role for an underestimated cell.
