AGE-ASSOCIATED LAMIN-B1 REDUCTION IN THE THYMIC EPITHELIAL CELLS AND ITS ROLE IN THYMIC INVOLUTION

Abstract

As a major component of the nuclear lamina, the type V intermediate filament proteins called lamins are important for the structure and function of the nucleus. Lamins are subdivided into A- and B-types. B-type lamins are implicated in the regulation of many aspects of nuclear function. However, the role of lamins in the context of adult organ maintenance and tissue aging remains largely unknown. Thymic involution, which is an age-related regression of the thymus, causes a decline in naive T cell production and is mainly responsible for immune senescence. The underlying mechanism for this process is still poorly understood. I developed a novel flow cytometry based method to quantify the protein level of nuclear lamins in vivo. By applying this new tool to the thymus, the primary immune organ for T-cell development, I identified an age-associated reduction of lamin-B1 in thymic epithelial cells (TECs). I further demonstrated that macrophage- and dendritic cell-derived proinflammatory cytokines led to lamin-B1 reduction in TECs via cellular senescence. I found that TEC-specific deletion of Lmnb1, but not Lmnb2 or Lmna, leads to thymic atrophy and a number of changes in the TEC compartment that are remarkably similar to reported age-related defects. I also demonstrated that lamin-B1 is required for proper antigen presentation in TECs and that lamin-B1 deficiency in TECs leads to inefficient positive and negative selection of T cells. My RNA-seq data strongly suggest that Lmnb1-loss-mediated transcriptome change contributes, at least in part, to the age-associated change in the transcriptional program in TECs and that this in turn leads to the observed degenerative phenotypes.