MATURE NEUTROPHILS AND GRANULOCYTIC PROGENITORS ISOLATED FROM PBSC DONORS DIFFERENTLY MODULATE T CELL FUNCTIONS

It is commonly accepted that neutrophils do not represent a population of short-lived terminally differentiated cells as previously thought. Indeed, the existence of distinct neutrophil subsets with functional and phenotypic heterogeneity has recently been documented in both mice and humans; particularly there is a general consensus also on the definition of human neutrophil subsets as “immunosuppressive”, based on their ability to suppress T cell responses, but still the phenotypes and mechanisms reported for these cells are very diverse. To address this issue and to gain further understanding on the phenotype and maturation/activation status of human immunosuppressive neutrophil subsets, in this study we isolated low density (LD) and normal density (ND) CD66b+ granulocytes from the peripheral blood of normal volunteers receiving G-CSF administration for hematopoietic stem cell mobilization (peripheral blood stem cell donors, PBSCs, or G-CSF-mobilized donors), in which the presence of G-MDSCs has been reported before. Importantly, in order to be able to clearly distinguish among the mature and immature neutrophil components present within the different LD and ND CD66b+ cell fractions, we evaluated the expression of antigen XY** whose expression, among granulocytes, is specific for mature/segmented neutrophils at the latest stages of differentiation. Interestingly, we found that LD and ND CD66b+ antigen XY+ mature neutrophils from G-CSF-mobilized donors inhibited T cell proliferation via CD18-cell contact dependent mechanism and arginase I release. By contrast, CD66b+ antigen XY- immature granulocytes from G-CSF-mobilized donors manifested an opposite behavior, as they enhanced T cell responses via CD18-contact dependent mechanisms. Overall, our study highlight the extreme importance of carefully characterizing the phenotype and the maturation/activation status of the different subsets of CD66b+ cells present in inflammatory conditions, such infections, autoimmune disease and cancer, in order to consider the manipulation of the function of these cells for clinical intervention. **as the data reported in this thesis are still unpublished, I will define as “antigen XY” the molecule we utilized throughout this study to distinguish mature neutrophils from immature granulocyte populations.