The generation of new neurons and glia from a precursor stem cell appears to take place in the adult brain. However, new neurons generated in the dentate gyrus decline sharply with age and to an even greater extent in neurodegenerative diseases. Here we raise the question whether peripheral immune mechanisms can generate immunity to such deficits in neuronal repair. We demonstrate that in contrast to primarily innate immunity cytokines, such as interleukin-6 and tumor necrosis factor-alpha, the adaptive immunity cytokine IFN-gamma enhances neurogenesis in the dentate gyrus of adult mice and improves the spatial learning and memory performance of the animals. In older mice, the effect of IFN-gamma is more pronounced in both wild-type mice and mice with Alzheimer's-like disease and is associated with neuroprotection. In addition, IFN-gamma reverses the increase in oligodendrogenesis observed in a mouse model of Alzheimer's disease. We demonstrate that limited amounts of IFN-gamma in the brain shape the neuropoietic milieu to enhance neurogenesis, possibly representing the normal function of the immune system in controlling brain inflammation and repair.

SummaryAlzheimer's disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid b-protein (Ab) peptides and neurofibrillary tangles in the brain associated with glial activation and synaptotoxicity. In addition, AD involves peripheral and brain endogenous inflammatory processes that appear to enhance disease progression. More than a decade ago a new therapeutic paradigm emerged for AD, namely the activation of the adaptive immune system directly against the self-peptide Ab, aimed at lowering its accumulation in the brain. This was the first time that a brain peptide was used to vaccinate human subjects in a manner similar to classic viral or bacterial vaccines. The vaccination approach has taken several forms, from initially active to passive and then back to modified active vaccines. As the first two approaches to date failed to show sufficient efficacy, the last is presently being evaluated in ongoing clinical trials. The present review summarizes the immunogenic characteristics of Ab in humans and mice and discusses past, present and future Ab-based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the pathogenesis and the general decline in T-cell responsiveness evident in the disease.

Stress activates the hypothalamic-pituitary-adrenocortical axis to promote the release of corticosterone (CORT), which consequently suppresses pathogenic stimulation of the immune system. Paradoxically, however, stress often promotes autoimmunity through yet unknown mechanisms. Here we investigated how chronic variable stress (CVS), and the associated alterations in CORT levels, affect the susceptibility to experimental autoimmune encephalomyelitis (EAE) in female and male C57BL/6 mice. Under baseline (nonstressed) conditions, females exhibited substantially higher CORT levels and an attenuated EAE with less mortality than males. However, CVS induced a significantly worsened EAE in females, which was prevented if CORT signaling was blocked. In addition, females under CVS conditions showed a shift toward proinflammatory Th1/Th17 versus Th2 responses and a decreased proportion of CD4 + CD25 + Treg cells. This demonstrates that whereas C57BL/6 female mice generally exhibit higher CORT levels and an attenuated form of EAE than males, they become less responsive to the immunosuppressive effects of CORT under chronic stress and thereby prone to a higher risk of destructive autoimmunity.Keywords: CD4 T cells r Chronic stress r Corticosterone r EAE Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt has been well established that stress may substantially affect the homeostatic regulation of the immune system [1][2][3]. In most Correspondence: Dr. Alon Monsonego e-mail: alonmon@bgu.ac.il animal models studied thus far, stressful triggers such as fear, maternal deprivation, social threat, or physiological challenge have been shown to induce immunosuppression associated with increased susceptibility to allergies and infectious diseases [1,4,5]. These effects are mediated by the hypothalamic-pituitary-adrenal (HPA) axis, a complex network linking the nervous, endocrine and immune systems [6,7].The HPA axis can be triggered by stress or by proinflammatory cytokines (e.g. IL-1, IL-6, and TNF-α) to ultimately result in C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 758-769 Immunomodulation 759 the secretion of corticosterone (CORT) from the adrenal glands to the circulation [8]. CORT, in turn, acts to suppress the activation, proliferation, and trafficking of immune cells [9,10] and plays a role in autoimmune regulation via shifting from Th1/Th17 pro-inflammatory to Th2 antiinflammatory responses [11][12][13]. Indeed, previous studies have shown that rats producing lower CORT levels (e.g. due to genetic manipulation or adrenalectomy) are more susceptible to pathogenic autoimmunity [14]. CORT is therefore often used as an immunosuppressor in the clinical treatment of inflammatory and autoimmune diseases [9,15,16]. Regardless of the immunosuppressive effects of CORT, chronic exposure to stress has also been linked with relapse of autoimmune diseases such as multiple sclerosis [17,18] and psoriasis [19,2...

Chronic low-grade inflammation and reduced lymphocyte potency are implicated in the pathogenesis of major illnesses associated with aging. Whether this immune phenotype results from a loss of cell-mediated regulation or intrinsic dysregulated function of effector T cells (Teffs) requires further research. Here, we report that, as compared with young C57BL6 mice, old mice show an increased frequency of CD4+CD62L− Teffs with a dysregulated activated phenotype and markedly increased effector functions. Analysis of the frequency and suppressive function of CD4+FoxP3+ regulatory T cells (Tregs) indicates an increase in the frequency of FoxP3+ T cells with aging which, however, occurs within the CD4+CD25− T cells. Furthermore, whereas Tregs from young and old mice similarly suppress Teffs from young mice, both have a compromised suppressive capacity of Teffs from old mice, a phenomenon which is partially recovered in the presence of IL-2-producing CD4+CD62L+ non-Teffs. Finally, we observed that Teff subsets from old mice are enriched with IL-17A-producing T cells and exhibit intrinsically dysregulated expression of genes encoding cell-surface molecules and transcription factors, which play a key role in T-cell activation and regulation. We, thus, demonstrate an age-related impairment in the regulation of effector CD4 T cells, which may underlie the higher risk for destructive inflammation associated with aging.