Schlafen, a New Family of Growth Regulatory Genes that Affect Thymocyte Development

AbstractThe Schlafen (Slfn) family of genes are differentially regulated during thymocyte maturation and are preferentially expressed in the lymphoid tissues. Ectopic expression of the prototype member Slfn1 early in the T lineage profoundly alters cell growth and development. In these mice, the DP thymocytes fail to complete maturation, and, depending on the transgene dosage, the number of thymocytes is reduced to 1%–30% of normal. Furthermore, expression of the Schlafen family members in fibroblasts and thymoma cells either retards or ablates cell growth. The conceptual protein sequences deduced for each of the family members have no similarity to characterized proteins and must therefore participate in a heretofore unknown regulatory mechanism guiding both cell growth and T cell development

Atypical PKC-iota Controls Stem Cell Expansion via Regulation of the Notch Pathway

SummaryThe number of stem/progenitor cells available can profoundly impact tissue homeostasis and the response to injury or disease. Here, we propose that an atypical PKC, Prkci, is a key player in regulating the switch from an expansion to a differentiation/maintenance phase via regulation of Notch, thus linking the polarity pathway with the control of stem cell self-renewal. Prkci is known to influence symmetric cell division in invertebrates; however a definitive role in mammals has not yet emerged. Using a genetic approach, we find that loss of Prkci results in a marked increase in the number of various stem/progenitor cells. The mechanism used likely involves inactivation and symmetric localization of NUMB, leading to the activation of NOTCH1 and its downstream effectors. Inhibition of atypical PKCs may be useful for boosting the production of pluripotent stem cells, multipotent stem cells, or possibly even primordial germ cells by promoting the stem cell/progenitor fate

Affinity and dose of TCR engagement yield proportional enhancer and gene activity in CD4+ T cells.

Affinity and dose of T cell receptor (TCR) interaction with antigens govern the magnitude of CD4+ T cell responses, but questions remain regarding the quantitative translation of TCR engagement into downstream signals. We find that while the response of mouse CD4+ T cells to antigenic stimulation is bimodal, activated cells exhibit analog responses proportional to signal strength. Gene expression output reflects TCR signal strength, providing a signature of T cell activation. Expression changes rely on a pre-established enhancer landscape and quantitative acetylation at AP-1 binding sites. Finally, we show that graded expression of activation genes depends on ERK pathway activation, suggesting that an ERK-AP-1 axis plays an important role in translating TCR signal strength into proportional activation of enhancers and genes essential for T cell function

FOXO transcription factors throughout T cell biology

Abstract | The outcome of an infection with any given pathogen varies according to the dosage and route of infection, but, in addition, the physiological state of the host can determine the efficacy of clearance, the severity of infection and the extent of immunopathology. Here we propose that the forkhead box O (FOXO) transcription factor family -which is central to the integration of growth factor signalling, oxidative stress and inflammation -provides connections between physical well-being and the form and magnitude of an immune response. We present a case that FOXO transcription factors guide T cell differentiation and function in a context-driven manner, and might provide a link between metabolism and immunity

A Role for FADD in T Cell Activation and Development

AbstractFADD is a cytoplasmic adapter molecule that links the family of death receptors to the activation of caspases during apoptosis. We have produced transgenic mice expressing a dominantly interfering mutant of FADD, lacking the caspase-dimerizing death effector domain, as well as mice overexpressing the poxvirus serpin, CrmA, an inhibitor of caspases downstream of FADD. While thymocytes from either line of mice were completely protected from CD95-dependent cytotoxicity, neither transgene afforded protection from apoptosis induced during thymocyte selection and neither led to the lymphoproliferative disorders associated with deficiencies in CD95. However, in FADD dominant negative (FADDdd) mice, early thymocyte development was retarded and peripheral lymphocyte pools were devoid of normal populations of T cells. We show that thymocytes and peripheral T cells from FADDdd display signaling anomalies, implying that FADD plays a previously uncharacterized role in T cell development and activation

The CD95 Receptor: Apoptosis Revisited

CD95 is the quintessential death receptor and, when it is bound by ligand, cells undergo apoptosis. Recent evidence suggests, however, that CD95 mediates not only apoptosis but also diverse nonapoptotic functions depending on the tissue and the conditions

Identification of RIP1 kinase as a specific cellular target of necrostatins

Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor–associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis

Mechanisms of necroptosis in T cells

In caspase 8-deficient mouse T cells, necroptosis occurs via a Ripk3- and Ripk1-dependent pathway independent of autophagy and programmed necrosis