Abstract
The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4/CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types.
Highlights
An understanding of the genetic requirements for T cell development has been built upon the analysis of murine and human T cell immunodeficiencies
An immunological challenge to induce inflammation, using the collagen-induced arthritis model, did not, identify any susceptibility to inflammatory disease (Supplementary Figure 7). These results demonstrate that Nup210 restrains IFNγ production under inappropriate, Th2-biased conditions, the deficiency effect remains subclinical even under inflammatory conditions. Both the Nup210 mutant mouse strain and the Nup210 knockout mouse strain manifested a disturbance in the peripheral T cells compartment, namely in the ratio of CD4 to CD8 T cells
The observation of general cell biology defects manifesting with T cell components is reoccurring [1], and may lie in the extraordinary rate of proliferating of early stage T cell differentiation in the thymus
Summary
An understanding of the genetic requirements for T cell development has been built upon the analysis of murine and human T cell immunodeficiencies These studies have identified genes that have roles in differentiation, function, maintenance, or homeostasis of T cells, with mutation leading to loss of the T cell population [1]. While complete loss of many of these genes would be anticipated to result in embryonic lethality, based on critical functions in cell biology, identified mutations tend to have T cell-specific defects. This observation is thought to be a result of selection bias, where only those point mutations mild enough to retain sufficient function for most cells result in viable offspring. Regardless, in multiple cases T cells have functioned as the “canary in the coal mine,” acting as a phenotyping read-out for mild mutations in critical cell biology genes
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