CD4+ effector T cells accelerate Alzheimer’s disease in mice
Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused...
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2021
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oai:doaj.org-article:9566142d7b6b497fa6e8c5d16550ee052021-11-21T12:39:53ZCD4+ effector T cells accelerate Alzheimer’s disease in mice10.1186/s12974-021-02308-71742-2094https://doaj.org/article/9566142d7b6b497fa6e8c5d16550ee052021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02308-7https://doaj.org/toc/1742-2094Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. Methods In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb–KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. Results The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. Conclusions These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs. Graphical AbstractJatin MachhiPravin YeapuriYaman LuEmma FosterRupesh ChikhaleJonathan HerskovitzKrista L. NammingaKatherine E. OlsonMai Mohamed AbdelmoatyJu GaoRolen M. QuadrosTomomi KiyotaLiang JingjingBhavesh D. KevadiyaXinglong WangYutong LiuLarisa Y. PoluektovaChannabasavaiah B. GurumurthyR. Lee MosleyHoward E. GendelmanBMCarticleAlzheimer’s disease (AD)Amyloid beta (Aβ)T cellEffector T cell (Teff)Regulatory T cell (Treg)APP/PS1 transgenic miceNeurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-23 (2021) |
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| topic |
Alzheimer’s disease (AD) Amyloid beta (Aβ) T cell Effector T cell (Teff) Regulatory T cell (Treg) APP/PS1 transgenic mice Neurology. Diseases of the nervous system RC346-429 |
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Alzheimer’s disease (AD) Amyloid beta (Aβ) T cell Effector T cell (Teff) Regulatory T cell (Treg) APP/PS1 transgenic mice Neurology. Diseases of the nervous system RC346-429 Jatin Machhi Pravin Yeapuri Yaman Lu Emma Foster Rupesh Chikhale Jonathan Herskovitz Krista L. Namminga Katherine E. Olson Mai Mohamed Abdelmoaty Ju Gao Rolen M. Quadros Tomomi Kiyota Liang Jingjing Bhavesh D. Kevadiya Xinglong Wang Yutong Liu Larisa Y. Poluektova Channabasavaiah B. Gurumurthy R. Lee Mosley Howard E. Gendelman CD4+ effector T cells accelerate Alzheimer’s disease in mice |
| description |
Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. Methods In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb–KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. Results The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. Conclusions These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs. Graphical Abstract |
| format |
article |
| author |
Jatin Machhi Pravin Yeapuri Yaman Lu Emma Foster Rupesh Chikhale Jonathan Herskovitz Krista L. Namminga Katherine E. Olson Mai Mohamed Abdelmoaty Ju Gao Rolen M. Quadros Tomomi Kiyota Liang Jingjing Bhavesh D. Kevadiya Xinglong Wang Yutong Liu Larisa Y. Poluektova Channabasavaiah B. Gurumurthy R. Lee Mosley Howard E. Gendelman |
| author_facet |
Jatin Machhi Pravin Yeapuri Yaman Lu Emma Foster Rupesh Chikhale Jonathan Herskovitz Krista L. Namminga Katherine E. Olson Mai Mohamed Abdelmoaty Ju Gao Rolen M. Quadros Tomomi Kiyota Liang Jingjing Bhavesh D. Kevadiya Xinglong Wang Yutong Liu Larisa Y. Poluektova Channabasavaiah B. Gurumurthy R. Lee Mosley Howard E. Gendelman |
| author_sort |
Jatin Machhi |
| title |
CD4+ effector T cells accelerate Alzheimer’s disease in mice |
| title_short |
CD4+ effector T cells accelerate Alzheimer’s disease in mice |
| title_full |
CD4+ effector T cells accelerate Alzheimer’s disease in mice |
| title_fullStr |
CD4+ effector T cells accelerate Alzheimer’s disease in mice |
| title_full_unstemmed |
CD4+ effector T cells accelerate Alzheimer’s disease in mice |
| title_sort |
cd4+ effector t cells accelerate alzheimer’s disease in mice |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/9566142d7b6b497fa6e8c5d16550ee05 |
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