Mast cell-deficient Kit(W-sh) "Sash" mutant mice display aberrant myelopoiesis leading to the accumulation of splenocytes that act as myeloid-derived suppressor cells

• Published in: The Journal of immunology (1950) 2013-06, Vol.190 (11), p.5534-5544
• Main Authors: Michel, Anastasija, Schüler, Andrea, Friedrich, Pamela, Döner, Fatma, Bopp, Tobias, Radsak, Markus, Hoffmann, Markus, Relle, Manfred, Distler, Ute, Kuharev, Jörg, Tenzer, Stefan, Feyerabend, Thorsten B, Rodewald, Hans-Reimer, Schild, Hansjörg, Schmitt, Edgar, Becker, Marc, Stassen, Michael
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antigens, Ly - metabolism; CD11b Antigen - metabolism; Female; Hematopoiesis, Extramedullary - genetics; Hematopoiesis, Extramedullary - immunology; Immunophenotyping; Mast Cells - immunology; Mast Cells - metabolism; Mice; Mice, Knockout; Mutation; Myeloid Cells - immunology; Myeloid Cells - metabolism; Myelopoiesis - genetics; Myelopoiesis - immunology; Neoplasm Transplantation; Neoplasms - immunology; Neoplasms - pathology; Proto-Oncogene Proteins c-kit - deficiency; Proto-Oncogene Proteins c-kit - genetics; Spleen - cytology; Spleen - immunology; Spleen - metabolism
• ISSN: 1550-6606
• DOI: 10.4049/jimmunol.1203355

Mast cell-deficient Kit(W-sh) "sash" mice are widely used to investigate mast cell functions. However, mutations of c-Kit also affect additional cells of hematopoietic and nonimmune origin. In this study, we demonstrate that Kit(W-sh) causes aberrant extramedullary myelopoiesis characterized by the expansion of immature lineage-negative cells, common myeloid progenitors, and granulocyte/macrophage progenitors in the spleen. A consistent feature shared by these cell types is the reduced expression of c-Kit. Populations expressing intermediate and high levels of Ly6G, a component of the myeloid differentiation Ag Gr-1, are also highly expanded in the spleen of sash mice. These cells are able to suppress T cell responses in vitro and phenotypically and functionally resemble myeloid-derived suppressor cells (MDSC). MDSC typically accumulate in tumor-bearing hosts and are able to dampen immune responses. Consequently, transfer of MDSC from naive sash mice into line 1 alveolar cell carcinoma tumor-bearing wild-type littermates leads to enhanced tumor progression. However, although it can also be observed in sash mice, accelerated growth of transplanted line 1 alveolar cell carcinoma tumors is a mast cell-independent phenomenon. Thus, the Kit(W-sh) mutation broadly affects key steps in myelopoiesis that may have an impact on mast cell research.