Immunological self tolerance is maintained at least in part by regulatory T (Treg) cells that actively and dominantly control potentially hazardous self-reactive T cells in the periphery. Antigens that stimulate self-reactive T cells may also activate natural Treg cells, thereby maintaining dominant self tolerance. Conversely, genetic anomalies or environmental agents that specifically or predominantly affect Treg cells cause or predispose to autoimmunity. With recent advances in our understanding of Treg cell development in the thymus and periphery and the molecular mechanism of Treg cell–mediated suppression, new ways of treating immunological diseases by targeting Treg cells at the cellular and molecular levels are envisaged.

Regulatory T cells exert checks and balances on self tolerance and autoimmunity

In eukaryotic cells, the endoplasmic reticulum is essential for the folding and trafficking of proteins that enter the secretory pathway. Environmental insults or increased protein synthesis often lead to protein misfolding in the organelle, the accumulation of misfolded or unfolded proteins - known as endoplasmic reticulum stress - and the activation of the adaptive unfolded protein response to restore homeostasis. If protein misfolding is not resolved, cells die. Endoplasmic reticulum stress and activation of the unfolded protein response help to determine cell fate and function. Furthermore, endoplasmic reticulum stress contributes to the aetiology of many human diseases.

Protein misfolding in the endoplasmic reticulum as a conduit to human disease

The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells for the storage and regulated release of calcium and as the entrance to the secretory pathway. Protein misfolding in the ER causes accumulation of misfolded proteins (ER stress) and activation of the unfolded protein response (UPR), which has evolved to maintain a productive ER protein-folding environment. Both ER stress and UPR activation are documented in many different human cancers. In this Review, we summarize the impact of ER stress and UPR activation on every aspect of cancer and discuss outstanding questions for which answers will pave the way for therapeutics.

The impact of the endoplasmic reticulum protein-folding environment on cancer development.

Indoleamine 2,3 dioxygenase and metabolic control of immune responses

The yeast cell wall is a strong, but elastic, structure that is essential not only for the maintenance of cell shape and integrity, but also for progression through the cell cycle. During growth and morphogenesis, and in response to environmental challenges, the cell wall is remodeled in a highly regulated and polarized manner, a process that is principally under the control of the cell wall integrity (CWI) signaling pathway. This pathway transmits wall stress signals from the cell surface to the Rho1 GTPase, which mobilizes a physiologic response through a variety of effectors. Activation of CWI signaling regulates the production of various carbohydrate polymers of the cell wall, as well as their polarized delivery to the site of cell wall remodeling. This review article centers on CWI signaling in Saccharomyces cerevisiae through the cell cycle and in response to cell wall stress. The interface of this signaling pathway with other pathways that contribute to the maintenance of cell wall integrity is also discussed.

https://www.genetics.org/content/genetics/189/4/1145.full.pdf

Regulation of Cell Wall Biogenesis in Saccharomyces cerevisiae: The Cell Wall Integrity Signaling Pathway

Foxo transcription factors regulate cell cycle progression, cell survival and DNA-repair pathways. Here we demonstrate that deficiency in Foxo3 resulted in greater expansion of T cell populations after viral infection. This exaggerated expansion was not T cell intrinsic. Instead, it was caused by the enhanced capacity of Foxo3-deficient dendritic cells to sustain T cell viability by producing more interleukin 6. Stimulation of dendritic cells mediated by the coinhibitory molecule CTLA-4 induced nuclear localization of Foxo3, which in turn inhibited the production of interleukin 6 and tumor necrosis factor. Thus, Foxo3 acts to constrain the production of key inflammatory cytokines by dendritic cells and to control T cell survival.

/pdf/transcription-factor-foxo3-controls-the-magnitude-of-t-cell-4cs6yv0n2z.pdf

Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells

https://www.cell.com/cell/pdf/S0092-8674(10)00624-0.pdf

A Surveillance Pathway Monitors the Fitness of the Endoplasmic Reticulum to Control Its Inheritance

The unfolded protein response (UPR) pathway helps cells cope with endoplasmic reticulum (ER) stress by activating genes that increase the ER's functional capabilities. We have identified a novel role for the UPR pathway in facilitating budding yeast cytokinesis. Although other cell cycle events are unaffected by conditions that disrupt ER function, cytokinesis is sensitive to these conditions. Moreover, efficient cytokinesis requires the UPR pathway even during unstressed growth conditions. UPR-deficient cells are defective in cytokinesis, and cytokinesis mutants activate the UPR. The UPR likely achieves its role in cytokinesis by sensing small changes in ER load and making according changes in ER capacity. We propose that cytokinesis is one of many cellular events that require a subtle increase in ER function and that the UPR pathway has a previously uncharacterized housekeeping role in maintaining ER plasticity during normal cell growth.

/pdf/a-novel-role-in-cytokinesis-reveals-a-housekeeping-function-3d7ygfa9o0.pdf

A novel role in cytokinesis reveals a housekeeping function for the unfolded protein response

Following endoplasmic reticulum (ER) stress, eukaryotic cells trigger a conserved signal transduction pathway called the unfolded protein response (UPR) that regulates the ER's capacity to perform protein folding according to cellular demand. In Saccharomyces cerevisiae, the UPR is initiated by Ire1, a type I transmembrane serine/threonine kinase/endoribonuclease, that senses unfolded protein levels within the ER in collaboration with the ER Hsp70-family member, BiP/Kar2. Here, we report on the characterization of the Yarrowia lipolytica Ire1 ortholog. Our results show that Sls1, a nucleotide exchange factor for BiP, has important functions in regulating ER stress and the interaction of BiP and Ire1. They suggest that Sls1 regulates this interaction, by stimulating the conversion of BiP from the ADP-bound to the ATP-bound state, which favors its interaction with Ire1. Moreover, we identified known and new partners for Ire1 using the Tandem Affinity Purification (TAP) approach.

Characterization of Ire1 in the yeast Yarrowia lipolytica reveals an important role for the Sls1 nucleotide exchange factor in unfolded protein response regulation

Anna Babour

Papers

Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells

A Surveillance Pathway Monitors the Fitness of the Endoplasmic Reticulum to Control Its Inheritance

A novel role in cytokinesis reveals a housekeeping function for the unfolded protein response

Characterization of Ire1 in the yeast Yarrowia lipolytica reveals an important role for the Sls1 nucleotide exchange factor in unfolded protein response regulation