CD4 T-cell aging exacerbates neuroinflammation in a late-onset mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons in the brain and spinal cord. Accumulating evidence suggests that ALS is not solely a neuronal cell- or brain tissue-autonomous disease and that neuroinflammation plays a key role in disease progression. Furthermore, whereas both CD4 and CD8 T cells were observed in spinal cords of ALS patients and in mouse models of the disease, their role in the neuroinflammatory process, especially considering their functional changes with age, is not fully explored. In this study, we revealed the structure of the CD4 T-cell compartment during disease progression of early-onset SOD1G93A and late-onset SOD1G37R mouse models of ALS. We show age-related changes in the CD4 T-cell subset organization between these mutant SOD1 mouse models towards increased frequency of effector T cells in spleens of SOD1G37R mice and robust infiltration of CD4 T cells expressing activation markers and the checkpoint molecule PD1 into the spinal cord. The frequency of infiltrating CD4 T cells correlated with the frequency of infiltrating CD8 T cells which displayed a more exhausted phenotype. Moreover, RNA-Seq and immunohistochemistry analyses of spinal cords from SOD1G37R mice with early clinical symptoms demonstrated immunological trajectories reminiscent of a neurotoxic inflammatory response which involved proinflammatory T cells and antigen presentation related pathways. Overall, our findings suggest that age-related changes of the CD4 T cell landscape is indicative of a chronic inflammatory response, which aggravates the disease process and can be therapeutically targeted.

Th1 polarization of T cells injected into the cerebrospinal fluid induces brain immunosurveillance.

Although CD4 T cells reside within the cerebrospinal fluid, it is yet unclear whether and how they enter the brain parenchyma and migrate to target specific Ags. We examined the ability of Th1, Th2, and Th17 CD4 T cells injected intracerebroventricularly to migrate from the lateral ventricles into the brain parenchyma in mice. We show that primarily Th1 cells cross the ependymal layer of the ventricle and migrate within the brain parenchyma by stimulating an IFN-γ-dependent dialogue with neural cells, which maintains the effector function of the T cells. When injected into a mouse model of Alzheimer's disease, amyloid-ß (Aß)-specific Th1 cells target Aß plaques, increase Aß uptake, and promote neurogenesis with no evidence of pathogenic autoimmunity or neuronal loss. Overall, we provide a mechanistic insight to the migration of cerebrospinal fluid CD4 T cells into the brain parenchyma and highlight implications on brain immunity and repair.

Chronic exposure to stress predisposes to higher autoimmune susceptibility in C57BL/6 mice: glucocorticoids as a double-edged sword.

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.

CD4 T cells in immunity and immunotherapy of Alzheimer's disease.

Alzheimer'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 ß-protein (Aß) 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 Aß, 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 Aß in humans and mice and discusses past, present and future Aß-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.

Randomised clinical trial: Psychological intervention improves work productivity and daily activity by reducing abdominal pain and fatigue in Crohn's disease.

BACKGROUND: Chronic abdominal pain and fatigue are characteristics of Crohn's disease (CD) and contribute to functional impairments. AIMS: To examine whether CD-tailored cognitive-behavioural and mindfulness intervention (COBMINDEX) is effective in reducing abdominal pain and fatigue in patients with CD and whether changes in abdominal pain and fatigue mediate any beneficial effects of COBMINDEX on impairments in work productivity and daily activities. METHODS: This is a secondary analysis of a parallel-group multicentre randomised controlled trial. Patients with mild-to-moderate CD (n = 142) were randomised into either intervention group receiving COBMINDEX, or control group receiving treatment-as-usual for 3 months followed by COBMINDEX. Complete data were collected from 120 patients (34.0 ± 10.7 years, 62.5% female, intervention = 60, control = 60). Analysis of covariance assessed group differences in 3-month follow-up scores, controlling for baseline scores. Multiple parallel mediation analysis assessed the proposed mechanisms for the entire sample. RESULTS: The intervention group demonstrated significantly lower levels of abdominal pain (F = 17.46, p < 0.001, η2 p  = 0.13), fatigue (F = 7.26, p = 0.008, η2 p  = 0.06) and impairments at work (F = 4.82, p = 0.032, η2 p  = 0.07) and daily activities (F = 6.26, p = 0.014, η2 p  = 0.05), compared with treatment-as-usual. Moreover, changes in abdominal pain and fatigue significantly mediated the beneficial effects of COBMINDEX on patients' work productivity (b = -9.90, SE = 2.86, 95% CI: -16.11 to -4.94) and daily activities (b = -9.65, SE = 1.91, 95% CI: -13.77 to 6.35), independent of changes in disease activity. CONCLUSIONS: COBMINDEX is effective at reducing abdominal pain and fatigue in patients with CD, which in turn leads to improvement in functioning. Clinicians should incorporate screening for severe abdominal pain and fatigue and consider offering cognitive-behavioural and mindfulness training. CLINICALTRIALS: gov, Number: NCT05085925. Ministry of Health in Israel (https://my.health.gov.il/CliniTrials/Pages/MOH_2020-02-24_008721.aspx).

Brain-immune axis regulation is responsive to cognitive behavioral therapy and mindfulness intervention: Observations from a randomized controlled trial in patients with Crohn's disease.

BACKGROUND AND AIMS: Crohn's disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the hypothalamus-pituitary-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) impacts their inflammatory process. METHODS: Circulating inflammatory markers and a wide range of psychological parameters related to stress and well-being were measured in CD patients before and after COBMINDEX. Inflammatory markers in CD patients were also compared to age- and sex-matched healthy controls (HCs). RESULTS: CD patients exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by interconnected inflammatory modules represented by IL-6, TNFα, IL-17, MCP-1 and IL-18. Notably, higher IL-18 levels correlated with higher score of stress and a lower score of wellbeing in CD patients. COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 and IFNα and negatively with those of MCP-1. Furthermore, inflammatory markers of CD patients at baseline predicted COBMINDEX efficacy, as higher levels of distinct cytokines and cortisol at baseline, correlated negatively with changes in disease activity (by Harvey-Bradshaw Index) and psychological distress (global severity index measure) following COBMINDEX. CONCLUSION: CD patients have a characteristic immunological profile that correlates with psychological stress, and disease severity. We suggest that COBMINDEX induces stress resilience in CD patients, which impacts their well-being, and their disease-associated inflammatory process.

Randomized Controlled Trial of Cognitive-Behavioral and Mindfulness-Based Stress Reduction on the Quality of Life of Patients With Crohn Disease.

BACKGROUND: Patients with Crohn disease have debilitating psychological symptoms, mental fatigue, and poor quality of life. Psychological intervention may improve these symptoms. METHODS: We performed a randomized parallel-group physician-blinded trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) on quality of life and psychological symptoms in adults with mild-moderate Crohn disease. COBMINDEX was taught by social workers in one-on-one video conferences over 3 months; quotidian home practice was mandated. RESULTS: Fifty-five COBMINDEX and 61 waitlist control patients completed the study; mean age was 33 years and 65% of participants were women. At 3 months, COBMINDEX patients had significantly reduced disease activity (per Harvey-Bradshaw Index score, C-reactive protein level, and calprotectin level), increased quality of life (Short Inflammatory Bowel Disease Questionnaire [SIBDQ] score increased from baseline 41 to 50; P < 0.001), decreased psychological symptoms (Global Severity Index [GSI], 0.98-0.70; P < 0.001), reduced fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue, 26-33; P < 0.001), and increased mindfulness disposition (Freiburg Mindfulness Inventory, 33-38; P < 0.001). Waitlist patients had a significant but small change in Harvey-Bradshaw Index, SIBDQ, and GSI scores, without improvement in fatigue or mindfulness. There were significant correlations (0.02 > P < 0.002) in COBMINDEX patients between baseline SIBDQ, GSI, Freiburg Mindfulness Inventory, and Functional Assessment of Chronic Illness Therapy-Fatigue scores with a relative change (baseline to 3 months) of the SIBDQ score, but none among waitlist patients. Predictors of relative change of the SIBDQ score in COBMINDEX patients included the GSI score (90% quantile; coefficient 0.52; P < 0.001), somatization (90%; 0.20; P = 0.001), depression (75%; 0.16; P = 0.03), and phobic anxiety (75%; 0.31; P = 0.008). CONCLUSIONS: COBMINDEX was effective in increasing patients' quality of life and reducing psychological symptoms and fatigue. Patients with severe baseline psychological symptoms benefited the most from COBMINDEX.

HLA-DR alleles in amyloid beta-peptide autoimmunity: a highly immunogenic role for the DRB1*1501 allele.

Active amyloid beta-peptide (Abeta) immunization of patients with Alzheimer's disease (AD) caused meningoencephalitis in approximately 6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of Abeta Ab responses, which correlate with the extent of Abeta clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing Abeta T cell reactivity, epitope specificity, and immunogenicity. Analysis of blood samples from 133 individuals disclosed that the abundant DR haplotypes DR15 (found in 36% of subjects), DR3 (in 18%), DR4 (12.5%), DR1 (11%), and DR13 (8%) were associated with Abeta-specific T cell responses elicited via distinct T cell epitopes within residues 15-42 of Abeta. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of Abeta challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-gamma and IL-17, and specific to the same T cell epitope as that observed in the HLA-DR15-bearing humans. Furthermore, following long-term therapeutic immunization of an AD mouse model bearing the DRB1*1501 allele, Abeta was effectively cleared from the brain parenchyma and brain microglial activation was reduced. The present study thus characterizes HLA-DR alleles directly associated with specific Abeta T cell epitopes and demonstrates the highly immunogenic properties of the abundant allele DRB1*1501 in a mouse model of AD. This new knowledge enables us to explore the basis for understanding the variations in naturally occurring Abeta-reactive T cells and Abeta immunogenicity among humans.

IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer's disease.

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.

BDNF-producing, amyloid ß-specific CD4 T cells as targeted drug-delivery vehicles in Alzheimer's disease.

BACKGROUND: The delivery of therapeutic proteins to selected sites within the central nervous system (CNS) parenchyma is a major challenge in the treatment of various neurodegenerative disorders. As brain-derived neurotrophic factor (BDNF) is reduced in the brain of people with Alzheimer's disease (AD) and its administration has shown promising therapeutic effects in mouse model of the disease, we generated a novel platform for T cell-based BDNF delivery into the brain parenchyma. METHODS: We generated amyloid beta-protein (Aß)-specific CD4 T cells (Aß-T cells), genetically engineered to express BDNF, and injected them intracerebroventricularly into the 5XFAD mouse model of AD. FINDINGS: The BDNF-secreting Aß-T cells migrated efficiently to amyloid plaques, where they significantly increased the levels of BDNF, its receptor TrkB, and various synaptic proteins known to be reduced in AD. Furthermore, the injected mice demonstrated reduced levels of beta-secretase 1 (BACE1)-a protease essential in the cleavage process of the amyloid precursor protein-and ameliorated amyloid pathology and inflammation within the brain parenchyma. INTERPRETATION: A T cell-based delivery of proteins into the brain can serve as a platform to modulate neurotoxic inflammation and to promote neuronal repair in neurodegenerative diseases.

CD4 T Cells Induce A Subset of MHCII-Expressing Microglia that Attenuates Alzheimer Pathology.

Microglia play a key role in innate immunity in Alzheimer disease (AD), but their role as antigen-presenting cells is as yet unclear. Here we found that amyloid ß peptide (Aß)-specific T helper 1 (Aß-Th1 cells) T cells polarized to secrete interferon-γ and intracerebroventricularly (ICV) injected to the 5XFAD mouse model of AD induced the differentiation of major histocompatibility complex class II (MHCII)+ microglia with distinct morphology and enhanced plaque clearance capacity than MHCII- microglia. Notably, 5XFAD mice lacking MHCII exhibited an enhanced amyloid pathology in the brain along with exacerbated innate inflammation and reduced phagocytic capacity. Using a bone marrow chimera mouse model, we showed that infiltrating macrophages did not differentiate to MHCII+ cells following ICV injection of Aß-Th1 cells and did not support T cell-mediated amyloid clearance. Overall, we demonstrate that CD4 T cells induce a P2ry12+ MHCII+ subset of microglia, which play a key role in T cell-mediated effector functions that abrogate AD-like pathology.

Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes.

Age-associated changes in CD4 T-cell functionality have been linked to chronic inflammation and decreased immunity. However, a detailed characterization of CD4 T cell phenotypes that could explain these dysregulated functional properties is lacking. We used single-cell RNA sequencing and multidimensional protein analyses to profile thousands of CD4 T cells obtained from young and old mice. We found that the landscape of CD4 T cell subsets differs markedly between young and old mice, such that three cell subsets-exhausted, cytotoxic, and activated regulatory T cells (aTregs)-appear rarely in young mice but gradually accumulate with age. Most unexpected were the extreme pro- and anti-inflammatory phenotypes of cytotoxic CD4 T cells and aTregs, respectively. These findings provide a comprehensive view of the dynamic reorganization of the CD4 T cell milieu with age and illuminate dominant subsets associated with chronic inflammation and immunity decline, suggesting new therapeutic avenues for age-related diseases.

The Choroid Plexus Functions as a Niche for T-Cell Stimulation Within the Central Nervous System.

The choroid plexus (CP) compartment in the ventricles of the brain comprises fenestrated vasculature and, therefore, it is permeable to blood-borne mediators of inflammation. Here, we explored whether T-cell activation in the CP plays a role in regulating central nervous system (CNS) inflammation. We show that CD4 T cells injected into the lateral ventricles adhere to the CP, transmigrate across its epithelium, and undergo antigen-specific activation and proliferation. This process is enhanced following peripheral immune stimulation and significantly impacts the immune signaling induced by the CP. Ex vivo studies demonstrate that T-cell harboring the CP through its apical surface is a chemokine- and adhesion molecule-dependent process. We suggest that, within the CNS, the CP serves an immunological niche, which rapidly responds to peripheral inflammation and, thereby, promotes two-way T-cell trafficking that impact adaptive immunity in the CNS.

Immunity and neuronal repair in the progression of Alzheimer's disease: a brief overview.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by memory loss and severe cognitive decline. The etiology of the disease has not been explored, although a significant body of evidence suggests that neuronal dysfunction is caused by hyperphosphorylation and intracellular accumulation of the Tau protein, extracellular accumulation of the amyloid beta-peptide (Abeta), and the associated chronic activation of glial cells. Clearance of toxic Abeta, apoptotic cells and debris from the brain together with induction of neuronal repair mechanisms may all take place partially throughout the progression of AD, but therapeutic approaches based on knowledge of these processes have been unsuccessfully developed. Here, we address the question of whether autoimmune mechanisms can be boosted to safely facilitate the above-mentioned clearance and neuronal repair in the AD brain. We have previously demonstrated that depending on genetic background, autoimmunity targeted to Abeta is already induced in elderly individuals and in patients with AD. We have shown in a mouse model of AD that given a preexisting proinflammatory milieu in the brain, immune cells can enter the brain tissue and participate in clearance of Abeta. Furthermore, the decline in cognitive functions and neurogenesis throughout the progression of AD may also be affected by autoimmune mechanisms operating in the periphery and in the brain. In light of the so-far unsuccessful anti-inflammatory approaches to treating AD, we suggest that boosting - rather than suppressing - the endogenous immune mechanisms induced in AD may enhance repair pathways in the brain, provided that this approach can be safely applied.

Accelerated microglial pathology is associated with Aß plaques in mouse models of Alzheimer's disease.

Microglia integrate within the neural tissue with a distinct ramified morphology through which they scan the surrounding neuronal network. Here, we used a digital tool for the quantitative morphometric characterization of fine cortical microglial structures in mice, and the changes they undergo with aging and in Alzheimer's-like disease. We show that, compared with microglia in young mice, microglia in old mice are less ramified and possess fewer branches and fine processes along with a slightly increased proinflammatory cytokine expression. A similar microglial pathology appeared 6-12 months earlier in mouse models of Alzheimer's disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to enhanced cognitive decline.

Active Aß vaccination fails to enhance amyloid clearance in a mouse model of Alzheimer's disease with Aß42-driven pathology.

Aß vaccination has been shown to induce remarkable clearance of brain amyloid plaques in mouse models of Alzheimer's disease (AD). However, the extent to which antibody-mediated Aß clearance is affected by predominant formation of Aß42 over Aß40 is unclear. Here we demonstrate for the first time that in a mouse model carrying the human APP mutations KM670/671NL and the human PS1 mutation P166L, Aß vaccination does not result in plaque clearance. This was in spite of the strong T- and B-cell immune responses evoked under the DR1501 genetic background and the activation of microglia at sites of Aß plaques. Our findings suggest the existence of antibody-resistant forms of Aß deposits in the brain consisting of primarily Aß42, and shed light on the mechanisms of antibody-dependent amyloid clearance as well as novel therapeutic strategies for AD.

Dendritic cells regulate amyloid-ß-specific T-cell entry into the brain: the role of perivascular amyloid-ß.

Amyloid-ß (Aß) accumulation in the brain is one of the hallmarks of Alzheimer's disease (AD). T-cell entry into vascular and parenchymal brain areas loaded with Aß has been observed with both beneficial as well as detrimental effects. Using a new AD mouse model, we studied the molecular mechanisms allowing CD4 T cells to specifically target Aß-loaded brain areas. We observed that following Aß immunization, CD11c+ dendritic cells (DCs) and CD4 T cells occurred primarily in the perivascular and leptomeningial spaces of cerebral vessels deposited with Aß. CD11c+ cells expressed high levels of the DC maturation markers DEC-205, MHC class II and CD86. Notably, the majority of cerebral blood vessels were found adjacent to Aß plaques, expressing high levels of the ICAM-1 and VCAM-1 adhesion molecules. We propose that the drainage of Aß to the leptomeningeal and perivascular spaces and its deposition there provide the antigenic source for DCs to stimulate Aß-specific T cells on their way to target amyloid plaques within the brain tissue.

Amyloid beta-HSP60 peptide conjugate vaccine treats a mouse model of Alzheimer's disease.

Active vaccination with amyloid beta peptide (Aß) to induce beneficial antibodies was found to be effective in mouse models of Alzheimer's disease (AD), but human vaccination trials led to adverse effects, apparently caused by exuberant T-cell reactivity. Here, we sought to develop a safer active vaccine for AD with reduced T-cell activation. We treated a mouse model of AD carrying the HLA-DR DRB1*1501 allele, with the Aß B-cell epitope (Aß 1-15) conjugated to the self-HSP60 peptide p458. Immunization with the conjugate led to the induction of Aß-specific antibodies associated with a significant reduction of cerebral amyloid burden and of the accompanying inflammatory response in the brain; only a mild T-cell response specific to the HSP peptide but not to the Aß peptide was found. This type of vaccination, evoking a gradual increase in antibody titers accompanied by a mild T-cell response is likely due to the unique adjuvant and T-cell stimulating properties of the self-HSP peptide used in the conjugate and might provide a safer approach to effective AD vaccination.

T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer's disease.

Patients with Alzheimer's disease (AD) exhibit substantial accumulation of amyloid-beta (Abeta) plaques in the brain. Here, we examine whether Abeta vaccination can facilitate the migration of T lymphocytes to specifically target Abeta plaques and consequently enhance their removal. Using a new mouse model of AD, we show that immunization with Abeta, but not with the encephalitogenic proteolipid protein (PLP), results in the accumulation of T cells at Abeta plaques in the brain. Although both Abeta-reactive and PLP-reactive T cells have a similar phenotype of Th1 cells secreting primarily IFN-gamma, the encephalitogenic T cells penetrated the spinal cord and caused experimental autoimmune encephalomyelitis (EAE), whereas Abeta T cells accumulated primarily at Abeta plaques in the brain but not the spinal cord and induced almost complete clearance of Abeta. Furthermore, while a single vaccination with Abeta resulted in upregulation of the phagocytic markers triggering receptors expressed on myeloid cells-2 (TREM2) and signal regulatory protein-beta1 (SIRPbeta1) in the brain, it caused downregulation of the proinflammatory cytokines TNF-alpha and IL-6. We thus suggest that Abeta deposits in the hippocampus area prioritize the targeting of Abeta-reactive but not PLP-reactive T cells upon vaccination. The stimulation of Abeta-reactive T cells at sites of Abeta plaques resulted in IFN-gamma-induced chemotaxis of leukocytes and therapeutic clearance of Abeta.

Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease.

Vaccination against amyloid beta-peptide (Abeta) has been shown to be successful in reducing Abeta burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although Abeta immunization did not show T cell infiltrates in the brain of these mice, an Abeta vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of Abeta-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong Abeta-specific T cell response is critically dependent on the immunizing T cell epitope and that epitopes differ depending on MHC genetic background. Moreover, we show that a single immunization with the dominant T cell epitope Abeta10-24 induced transient meningoencephalitis only in amyloid precursor protein (APP)-transgenic (Tg) mice expressing limited amounts of IFN-gamma under an myelin basic protein (MBP) promoter. Furthermore, immune infiltrates were targeted primarily to sites of Abeta plaques in the brain and were associated with clearance of Abeta. Immune infiltrates were not targeted to the spinal cord, consistent with what was observed in AD patients vaccinated with Abeta. Using primary cultures of microglia, we show that IFN-gamma enhanced clearance of Abeta, microglia, and T cell motility, and microglia-T cell immunological synapse formation. Our study demonstrates that limited expression of IFN-gamma in the brain, as observed during normal brain aging, is essential to promote T cell-mediated immune infiltrates after Abeta immunization and provides a model to investigate both the beneficial and detrimental effects of Abeta-specific T cells.