Essential cell-intrinsic requirement for GMDS in T cell development.

Fucosylation, a type of glycosylation, is the attachment of a fucose to -glycans, -glycans and glycolipids, and is critical for the post-translational regulation of many essential pathways. Here we describe a mouse strain with an -ethyl--nitrosourea-induced point mutation in the gene encoding guanosine diphosphate (GDP)-mannose 4,6-dehydratase (GMDS), an enzyme involved in the generation of GDP-fucose, a substrate for fucosylation. mice displayed growth retardation and increased postnatal mortality. Immunophenotyping of mice revealed reduced numbers of double positive (DP), CD4 single positive (SP) and CD8SP T cells, despite normal numbers of double negative (DN) cells in the thymus of mutant animals. Similarly, analysis of the thymus in mice reconstituted with bone marrow cells revealed a partial arrest at the DN stage of T cell development compared to animals transplanted with bone marrow cells. Furthermore, mixed chimeras showed that T cells were unable to compete with cells from the DP stage of T cell development in the thymus. This inability to compete resulted in the near absence of -derived peripheral T cells in recipient mice, while B cell subsets were present at broadly normal frequencies. These findings provide the first evidence of an essential cell-intrinsic requirement for GMDS in early T cell development in mice.