High K intake alleviates experimental autoimmune encephalomyelitis (EAE) and increases T regulatory cells.

Multiple sclerosis is believed to be triggered by the interplay between the environmental and genetic factors. In contrast to the Paleolithic diet, the modern Western diet is high in Na and low in K. The present study was undertaken to determine whether high K intake alleviated experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis.

NFAT5 contributes to the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and decrease of T regulatory cells in female mice.

Multiple sclerosis disproportionally affects women. The present study was undertaken to determine whether NFAT5 contributed to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, and if it did, whether the impact was sex associated. NFAT5 haplodeficiency reduced the disease severity only in female mice.

CD8+ T cells: The past and future of immune regulation.

Regulation of the adaptive immune response is critical for health. Regulatory activity can be found in multiple components of the immune system, however, the focus on particular components of the immune regulatory network has left many aspects of this critical immune component understudied. Here we review the evidence for activities of CD8+ T cells in immune homeostasis and regulation of autoimmune reactivity.

A novel CNS-homing peptide for targeting neuroinflammatory lesions in experimental autoimmune encephalomyelitis.

Using phage peptide library screening, we identified peptide-encoding phages that selectively home to the inflamed central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis (MS). A phage peptide display library encoding cyclic 9-amino-acid random peptides was first screened ex-vivo for binding to the CNS tissue of EAE mice, followed by in vivo screening in the diseased mice. Phage insert sequences that were present at a higher frequency in the CNS of EAE mice than in the normal (control) mice were identified by DNA sequencing.

Targeting antigen presentation in autoimmunity.

Autoimmune diseases are heterogeneous group of disorders that together represent an enormous societal and medical problem. CD4+ T cells have critical roles in the initiation and pathogenesis of autoimmune disease. As such, modulation of T cell activity has proven to have significant therapeutic effects in multiple autoimmune settings.

Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells.

Expanded polyclonal T regulatory cells (Tregs) offer great promise for the treatment of immune-mediated diseases. Inhibition by Tregs is under the control of the T-cell receptor (TCR). Therefore, we created Tregs with defined antigen specificity, using a recombinant T-cell receptor isolated from a myelin-basic protein specific T-cell clone of a multiple sclerosis (MS) patient (Ob2F3).

Progression of experimental autoimmune encephalomyelitis is associated with up-regulation of major sodium transporters in the mouse kidney cortex under a normal salt diet.

Recent demonstrations of exacerbation of experimental autoimmune encephalomyelitis (EAE) by high salt diets prompted us to study whether EAE stimulated Na absorption by the renal cortex, a primary regulatory site for Na balance, even under a normal NaCl diet. We found that as EAE progressed from mild to severe symptoms, there were parallel increases in the protein abundance of NHE3 and αENaC and the Na,K-ATPase activity with an affiliated elevation of its β1-subunit protein. These effects are associated with increases in the protein levels of the well-known regulators SGK1 and scaffold NHERF2, and phosphorylation of ERK1/2.

RGC-32 Promotes Th17 Cell Differentiation and Enhances Experimental Autoimmune Encephalomyelitis.

Th17 cells play a critical role in autoimmune diseases, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Response gene to complement (RGC)-32 is a cell cycle regulator and a downstream target of TGF-β that mediates its profibrotic activity. In this study, we report that RGC-32 is preferentially upregulated during Th17 cell differentiation.

Odorants specifically modulate chemotaxis and tissue retention of CD4+ T cells via cyclic adenosine monophosphate induction.

Retention of T cells within affected tissue is a critical component of adaptive immune inflammation. However, the mechanisms involved in T cell retention remain largely undefined. Previous studies revealed the capacity of cAMP signaling to regulate immune cell migration, as well as dynamic regulation of receptors that could induce cAMP production in immune cells.

Interferon gamma in autoimmunity: A complicated player on a complex stage.

Early views of autoimmune disease cast IFNγ as a prototypic pro-inflammatory factor. It is now clear that IFNγ is capable of both pro- and anti-inflammatory activities with the functional outcome dependent on the physiological and pathological setting examined. Here, the major immune modulatory activities of IFNγ are reviewed and current evidence for the impact of IFNγ on pathology and regulation of several autoimmune diseases and disease models is summarized.

Pre-existing central nervous system lesions negate cytokine requirements for regional experimental autoimmune encephalomyelitis development.

In region-specific forms of experimental autoimmune encephalomyelitis (EAE), lesion initiation is regulated by T-cell-produced interferon-γ (IFN-γ) resulting in spinal cord disease in the presence of IFN-γ and cerebellar disease in the absence of IFN-γ. Although this role for IFN-γ in regional disease initiation is well defined, little is known about the consequences of previous tissue inflammation on subsequent regional disease, information vital to the development of therapeutics in established disease states. This study addressed the hypothesis that previous establishment of regional EAE would determine subsequent tissue localization of new T-cell invasion and associated symptoms regardless of the presence or absence of IFN-γ production.

Myeloid derived suppressor cells in transplantation.

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of hematopoietic derived cell precursors that can suppress immune responses in a variety of inflammatory settings. Here we review recent studies detailing expansion of phenotypically and functionally disparate MDSC. Findings related to MDSC accumulation, activation, and mechanisms utilized in immune suppression are presented.

Generation, persistence and plasticity of CD4 T-cell memories.

The development of immune memory mediated by T lymphocytes is central to durable, long-lasting protective immunity. A key issue in the field is how to direct the generation and persistence of memory T cells to elicit the appropriate secondary response to provide protection to a specific pathogen. Two prevailing views have emerged; that cellular and molecular regulators control the lineage fate and functional capacities of memory T cells early after priming, or alternatively, that populations of memory T cells are inherently plastic and subject to alterations in function and/or survival at many stages during their long-term maintenance.

Prolonged antigen presentation is required for optimal CD8+ T cell responses against malaria liver stage parasites.

Immunization with irradiated sporozoites is currently the most effective vaccination strategy against liver stages of malaria parasites, yet the mechanisms underpinning the success of this approach are unknown. Here we show that the complete development of protective CD8+ T cell responses requires prolonged antigen presentation. Using TCR transgenic cells specific for the malaria circumsporozoite protein, a leading vaccine candidate, we found that sporozoite antigen persists for over 8 weeks after immunization--a remarkable finding since irradiated sporozoites are incapable of replication and do not differentiate beyond early liver stages.

Encephalitogenic T-cells increase numbers of CNS T-cells regardless of antigen specificity by both increasing T-cell entry and preventing egress.

This study utilized an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE) induction in mice to characterize the mechanisms involved in CNS accumulation of transferred and host T-cells. Using a flow cytometric technique, we examined phenotypic characteristics of CNS T-cells following disease initiation and the role of T-cell activation in CNS invasion and retention. Host T-cell activation increased cell recruitment and EAE severity.

IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease of the CNS characterized by disruption of the blood-brain barrier (BBB). This breach in CNS immune privilege allows undeterred trafficking of myelin-specific lymphocytes into the CNS where they induce demyelination. Although the mechanism of BBB compromise is not known, the chemokine CXCL12 has been implicated as a molecular component of the BBB whose pattern of expression is specifically altered during MS and which correlates with disease severity.

Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis.

The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-gamma. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-gamma deficient).

Host T cells are the main producers of IL-17 within the central nervous system during initiation of experimental autoimmune encephalomyelitis induced by adoptive transfer of Th1 cell lines.

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, has long been thought to be mediated by Th1 CD4(+) T cells. Using adoptive transfer techniques, transfer of CNS specific Th1 T cells was sufficient to induce EAE in naive mice. However, recent studies found a vital role for IL-17 in induction of EAE.

A little stress is good: IFN-gamma, demyelination, and multiple sclerosis.

The exact role(s) of the cytokine IFN-gamma in the demyelinating disease multiple sclerosis remain controversial, with evidence suggesting both detrimental and protective effects of the cytokine in MS and MS models such as EAE. The study by Lin and coworkers in this issue of the JCI produces evidence that protective effects of IFN-gamma on mature oligodendrocytes during EAE induction are mediated via activation of the pancreatic ER kinase (PERK), resulting in induction of the endoplasmic reticular stress response pathway (see the related article beginning on page 448). Modulation of this stress pathway has what we believe to be novel therapeutic potential for MS.

T-cell trafficking competence is required for CNS invasion.

T-cell invasion of the CNS is critical for the induction of a variety of autoimmune mediated neuronal diseases. We utilized blood-brain barrier (BBB) mediated exclusion of anti-CD4 antibody to define populations of encephalitogenic T-cells recovered from mouse CNS preparations as either CNS invasive or non-invasive. This separation of cells allowed flow cytometric examination of the kinetics of encephalitogenic T-cell entry past the BBB.

Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8+ T cells.

Previous reports have demonstrated clonal deletion of CD8(+) T cells during peripheral tolerance induction to tissue antigens. However, direct evidence demonstrating a causal connection between deletion and tolerance has not been reported because of model limitations in which the tissue antigens were expressed in vital organs. Thus, studies were initiated in a mouse model where expression of a membrane-bound ovalbumin fusion protein (mOVA) was driven by a prostate specific androgen regulated probasin promotor, providing restricted expression in a non-vital organ where antigen levels can be abrogated through androgen deprivation.

T-cell recognition of a prostate specific antigen is not sufficient to induce prostate tissue destruction.

Methods: The ability of CD8(+) T-cells to induce prostate inflammation was examined using a prostate ovalbumin expressing transgenic mouse (POET) and/or adoptive transfer of T-cell receptor (TCR) transgenic T-cells (OT-I) that specifically recognize ovalbumin. Localization of inflammatory cells to prostate tissue was examined following T-cell activation via endogenous prostatic antigen, recombinant type 5 adenovirus carrying the gene coding ovalbumin (Ad5-mOVA), or adoptive transfer of in vitro antigen stimulated OT-I cells.

Results: Ovalbumin specific OT-I cells were activated by autologous prostate antigen and trafficked to the prostate, but did not induce inflammation unless present in overwhelming numbers ( approximately 65% of CD8(+) T-cells).

Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments.

Platelets are highly reactive components of the circulatory system with well-documented hemostatic function. Recent studies extend platelet function to modulation of local inflammatory events through the release of chemokines, cytokines, and a number of immunomodulatory ligands, including CD154. We hypothesized that platelet-derived CD154 modulates adaptive immunity.