Massive Rigid String Model and its Supersymmetric Extension

We discuss a rigid string model proposed by Casalbuoni and Longhi. Constraints for the massive states are solved to find the physical states and the mass spectrum. We also find its supersymmetric extension with the kappa symmetry. The supersymmetry transformations are found starting from on-shell transformations using the Dirac bracket.Comment: 16 pages with no fugure, references adde

Naive CD8+ T cells differentiate into protective memory-like cells after IL-2–anti–IL-2 complex treatment in vivo

An optimal CD8+ T cell response requires signals from the T cell receptor (TCR), co-stimulatory molecules, and cytokines. In most cases, the relative contribution of these signals to CD8+ T cell proliferation, accumulation, effector function, and differentiation to memory is unknown. Recent work (Boyman, O., M. Kovar, M.P. Rubinstein, C.D. Surh, and J. Sprent. 2006. Science. 311:1924–1927; Kamimura, D., Y. Sawa, M. Sato, E. Agung, T. Hirano, and M. Murakami. 2006. J. Immunol. 177:306–314) has shown that anti–interleukin (IL) 2 monoclonal antibodies that are neutralizing in vitro enhance the potency of IL-2 in vivo. We investigated the role of IL-2 signals in driving CD8+ T cell proliferation in the absence of TCR stimulation by foreign antigen. IL-2 signals induced rapid activation of signal transducer and activator of transcription 5 in all CD8+ T cells, both naive and memory phenotype, and promoted the differentiation of naive CD8+ T cells into effector cells. IL-2–anti–IL-2 complexes induced proliferation of naive CD8+ T cells in an environment with limited access to self–major histocompatibility complex (MHC) and when competition for self-MHC ligands was severe. After transfer into wild-type animals, IL-2–activated CD8+ T cells attained and maintained a central memory phenotype and protected against lethal bacterial infection. IL-2–anti–IL-2 complex–driven memory-like CD8+ T cells had incomplete cellular fitness compared with antigen-driven memory cells regarding homeostatic turnover and cytokine production. These results suggest that intense IL-2 signals, with limited contribution from the TCR, program the differentiation of protective memory-like CD8+ cells but are insufficient to guarantee overall cellular fitness

Gateway Reflex: A Neuro-Immune Crosstalk for Organ-Specific Disease Development

Homeostasis of the central nervous system (CNS) is strictly regulated by a unique structure of blood vessels, the blood-brain barrier (BBB). Experimental and clinical evidence has revealed that abnormalities in the BBB in chronic inflammatory diseases such as multiple sclerosis (MS). By using an animal model of MS, we identified novel neuro-immune crosstalk to explain how pathogenic immune cells enter the CNS to disrupt its homeostasis, a phenomenon we named the gateway reflex. Regional neural inputs such as gravity, electricity, pain or chronic stress cause specific neural activation to create a gateway of immune cells, particularly pathogenic ones, at specific blood vessels. Moreover, the recently discovered stress-induced gateway reflex uncovered a stress-induced neural link between the brain, gastrointestine, and heart. Thus, the gateway reflex is critical for the homeostasis of various organs, and aberrant activation of neural pathways by the gateway reflex disrupts normal organ homeostasis. The inflammatory reflex is another mechanism for local neuro-immune interactions. It potently exerts a cholinergic anti-inflammatory effect on various disease conditions. In this section, we discuss emerging roles for local neuro-immune interactions, with a special focus on the gateway reflex

The Gateway Reflex, a Novel Neuro‐immune Interaction, is Critical for the Development of Mouse Multiple Sclerosis (MS) Models

The central nervous system (CNS) is an immune‐privileged tissue protected by the brain–blood barrier (BBB), which limits the absorption of substances and cells from blood flow. In the case of inflammatory diseases in the CNS, such as multiple sclerosis (MS), however, autoreactive T cells that attack brain autoantigens, including myelin proteins, circumvent the BBB. Despite the wide distribution of brain autoantigens, demyelination often occurs as discrete foci. This fact suggests that there might be a certain cue that guides autoreactive T cells to particular site(s) in the CNS. In other words, there exists a mechanism that facilitates a site‐specific accumulation of autoreactive T cells in the CNS. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we identified dorsal vessels of the fifth lumbar (L5) spinal cord as the initial entry site of immune cells. The formation of a gateway for immune cells is defined by local neural stimulations. For example, neural stimulation by gravity creates this gateway by increasing the expression of chemokines that attract autoreactive T cells. Regional neural activation by the other stimuli, such as electric pulses or pain sensation, also induces gateway formation, but at different blood vessels via chemokine expression. These neuro‐immune interactions are examples of the gateway reflex and are extensively reviewed in this chapter

Hepatic Interleukin-7 Expression Regulates T Cell Responses

SummarySystemic cytokine activity in response to Toll-like receptor (TLR) signaling induces the expression of various proteins in the liver after infections. Here we show that Interleukin-7 (IL-7), the production of which was thought to occur at a constant rate in vivo, was a hepatically expressed protein that directly controled T cell responses. Depletion of IL-7 expression in the liver abrogated several TLR-mediated T cell events, including enhanced CD4+ T cell and CD8+ T cell survival, augmented CD8+ T cell cytotoxic activity, and the development of experimental autoimmune encephalitis, a Th17 cell-mediated autoimmune disease. Thus, T cell responses are regulated by hepatocyte-derived IL-7, which is expressed in response to TLR signaling in vivo. We suggested that TLR-induced IL-7 expression in the liver, which is an acute-phase response, may be a good diagnostic and therapeutic target for efficient vaccine developments and for conditions characterized by TLR-mediated T cell dysregulation, including autoimmune diseases

A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis

We generated a mouse line in which the src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130F759/F759). The gp130F759/F759 mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130F759/F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease

EVI1 triggers metabolic reprogramming associated with leukemogenesis and increases sensitivity to L-asparaginase

Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1+MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1+ leukemia cells may aid development of treatments for EVI1+MF9 refractory leukemia

Disease-Association Analysis of an Inflammation-Related Feedback Loop

SummaryThe IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets

Local microbleeding facilitates IL-6– and IL-17–dependent arthritis in the absence of tissue antigen recognition by activated T cells

Local microbleeding induces the accumulation of Th17 cells and the development of IL-17– and IL-6–dependent arthritis in the absence of cognate antigen recognition by CD4+ T cells