The senescence-associated secretory phenotype (SASP) has attracted attention as a mechanism that connects cellular senescence to tissue dysfunction, and specific SASP factors have been identified as systemic pro-aging factors. However, little is known about the age-dependent changes in the secretory properties of stem cells. Young, but not old, mesenchymal stem/stromal cells (MSCs) are a well-known source of critical regenerative factors, but the identity of these factors remains elusive. In this study, we identified growth differentiation factor 6 (Gdf6; also known as Bmp13 and CDMP-2) as a regenerative factor secreted from young MSCs. The expression of specific secretory factors, including Gdf6, was regulated by the microRNA (miRNA) miR-17, whose expression declined with age. Upregulation of Gdf6 restored the osteogenic capacity of old MSCs in vitro and exerted positive effects in vivo on aging-associated pathologies such as reduced lymphopoiesis, insufficient muscle repair, reduced numbers of neural progenitors in the brain, and chronic inflammation. Our results suggest that manipulation of miRNA could enable control of the SASP, and that regenerative factors derived from certain types of young cells could be used to treat geriatric diseases.

Temporal down-regulation of the CD8 co-receptor after receiving positive-selection signals has been proposed to serve as an important determinant to segregate helper versus cytotoxic lineages by generating differences in the duration of TCR signaling between MHC-I and MHC-II selected thymocytes. By contrast, little is known about whether CD8 also modulates TCR signaling engaged by the non-classical MHC-I–like molecule, CD1d, during development of invariant natural killer T (iNKT) cells. Here, we show that constitutive transgenic CD8 expression resulted in enhanced differentiation of innate memory-like CD8+ thymocytes in both a cell-intrinsic and cell-extrinsic manner, the latter being accomplished by an increase in the IL-4–producing iNKT2 subset. Skewed iNKT2 differentiation requires cysteine residues in the intracellular domain of CD8α that are essential for transmitting cellular signaling. Collectively, these findings shed a new light on the relevance of CD8 down-regulation in shaping the balance of iNKT-cell subsets by modulating TCR signaling.

Loss of Runx/Cbfβ complexes during DC development leads to a loss of gut CD103+CD11b+ cDC2s, which was accompanied with impaired differentiation of both Rorγt+ Th17 cells and type 3 Rorγt+ Treg cells.

During differentiation of CD4CD8 double-positive (DP) thymocytes into the CD4CD8 single-positive (CD8SP) thymocytes committed to the cytotoxic T cell lineage, transcription is temporally terminated after positive selection and is subsequently reinitiated, a process known as coreceptor reversal. Despite the identification of a transcriptional enhancer in the gene that directs reporter transgene expression specifically in CD8SP thymocytes, the molecular mechanisms controlling reactivation of the gene are not fully understood. Here, we show that, after positive selection, hCD2 reporter expression from the locus, which was generated by insertion of hCD2 cDNA into the first exon of the gene, requires the incorporation of intron sequences into the transcript. The presence of polyadenylation signals after hCD2 cDNA inhibited hCD2 expression in mature CD8 T cells, whereas hCD2 expression in DP thymocytes recapitulated the expression. Incorporation of the endogenous short intron structure and heterologous intron structure of the locus restored hCD2 expression in mature CD8 T cells in a variegated manner. Interestingly, stage-specific DNA demethylation was impaired in reporter alleles that failed to express hCD2 in CD8 T cells, and intron sequences lacking RNA splicing signals still restored hCD2 expression. These observations indicate that "intron-mediated enhancement" is involved in a stage-specific reactivation of the locus harboring hCD2 cDNA. However, the gene was transcribed in mature CD8 T cells, albeit at a lower level, from a mutant locus lacking intron structures, suggesting that protein-coding sequences in transcripts affect sensitivity to intron-mediated enhancement.

The genome organizer, special AT-rich binding protein-1 (SATB1), functions to globally regulate gene networks during primary T cell development and plays a pivotal role in lineage specification in CD4+helper-, CD8+cytotoxic-, and FOXP3+regulatory-T cell subsets. However, it remains unclear howSatb1gene expression is controlled, particularly in effector T cell function. Here, by using a novel reporter mouse strain expressing SATB1-Venus and genome editing, we have identified acis-regulatory enhancer, essential for maintainingSatb1expression specifically in TH2 cells. This enhancer is occupied by STAT6 and interacts withSatb1promoters through chromatin looping in TH2 cells. Reduction ofSatb1expression, by the lack of this enhancer, resulted in elevated IL-5 expression in TH2 cells. In addition, we found thatSatb1is induced in activated group 2 innate lymphoid cells (ILC2s) through this enhancer. Collectively, these results provide novel insights into howSatb1expression is regulated in TH2 cells and ILC2s during type 2 immune responses.