MTORC1 (mammalian target of rapamycin complex 1) controls transcriptional programs that determine CD8+ cytolytic T cell (CTL) fate. In some cell systems, mTORC1 couples phosphatidylinositol-3 kinase (PI3K) and Akt to the control of glucose uptake and glycolysis. However, PI3K–Akt-independent mechanisms control glucose metabolism in CD8+ T cells, and the role of mTORC1 has not been explored. The present study now demonstrates that mTORC1 activity in CD8+ T cells is not dependent on PI3K or Akt but is critical to sustain glucose uptake and glycolysis in CD8+ T cells. We also show that PI3K- and Akt-independent pathways mediated by mTORC1 regulate the expression of HIF1 (hypoxia-inducible factor 1) transcription factor complex. This mTORC1–HIF1 pathway is required to sustain glucose metabolism and glycolysis in effector CTLs and strikingly functions to couple mTORC1 to a diverse transcriptional program that controls expression of glucose transporters, multiple rate-limiting glycolytic enzymes, cytolytic effector molecules, and essential chemokine and adhesion receptors that regulate T cell trafficking. These data reveal a fundamental mechanism linking nutrient and oxygen sensing to transcriptional control of CD8+ T cell differentiation.

Recent genetic and molecular studies of hair follicle (HF) biology have provided substantial insight; however, the molecular data, including expression patterns, cannot be properly appreciated without an understanding of the basic cellular rearrangements and interactions that underpin HF cyclic transformations. We present a novel interpretation of the major cellular processes that take place during HF cycling – the hypothesis of hair follicle predetermination. This hypothesis is an extension of previous models of HF cellular kinetics but has two critical modifications: the dual origin of the cycling portion of the HF, and the timing of the recruitment of stem cells. A compilation of evidence suggests that the ascending portion of the HF (hair shaft and inner root sheath) arises not from bulge-located HF stem cells that contribute to the formation of only the outer root sheath (ORS), but instead from the germinative cells localized in the secondary hair germ. In middle anagen, upon completion of the downward growth of the HF, cells derived from the bulge region migrate downward along the ORS to reside at the periphery of the HF bulb as a distinct, inactive cell population that has specific patterns of gene expression - ‘the lateral disc’. These cells survive catagen-associated apoptosis and, under the direct influence of the follicular papilla (FP), transform into the hair germ and acquire the ability to respond to FP signaling and produce a new hair. Thus, we propose that the specific sensitivity of germ cells to FP signaling and their commitment to produce the ascending HF layers are predetermined by the previous hair cycle during the process of transformation of bulge-derived lateral disc cells into the secondary hair germ.

The cornified layer is a compacted lattice of lipid-embedded corneocytes that provides an organism's barrier to the external environment. Cornification is the final differentiative step for epidermal keratinocytes and involves dramatic cell condensation before death. Using conditional gene deletion in mice, we identified the transcriptional repressor Blimp-1 (B lymphocyte-induced maturation protein-1) as an important regulator of keratinocyte transition from the granular to the cornified layer. More than 250 genes are misregulated in conditional knockout epidermis, including those encoding transcription factors, signal transduction components, proteinases, and enzymes involved in lipid metabolism. Steady-state mRNA and ChIP analyses of a subset of these genes provide evidence that nfat5 , fos , prdm1 , and dusp16 are novel direct targets of Blimp-1. Identifying nfat5 as a target of Blimp-1 repression indicates that cornification involves suppression of normal osmotic regulation in granular cells. Consistently, conditional knockout mice have delayed barrier formation as embryos, enlarged granular layer cells and corneocytes, and a morphologically abnormal cornified layer. These studies provide insight into cornification, identifying transcriptional regulatory circuitry and indicating the importance of blocking osmotic homeostasis.