Encephalitogenic and Regulatory CD8 T Cells in Multiple Sclerosis and Its Animal Models

Mockus, Taryn E; Munie, Ashley; Atkinson, Jeffrey R.; Segal, Benjamin M.

doi:10.4049/jimmunol.2000797

Cited by 28 publications

(14 citation statements)

References 109 publications

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“…Interestingly, some of the transcripts upregulated in cluster 1 microglia from middle-aged mice are involved in the assembly and function of proteasomes and processing of MHC Class I restricted peptides. Although our model of EAE is CD4 + T cell-driven, CD8 + T cells are more prevalent than CD4 + T cells in human MS lesions, including in the chronic active lesions that are typical of pMS (30–32). The emergence of microglia particularly well-equipped to activate CD8 + T cells might be relevant to the pathogenesis of pMS.…”

Section: Discussionmentioning

confidence: 97%

Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

Atkinson

Jerome

Sas

et al. 2021

Preprint

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Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing remitting MS (RRMS) typically presents in the third or fourth decade, while the mean age of presentation of progressive MS (pMS) is 45 years old. Here we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+ Th17 cells, is more severe, and less like to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils are more abundant, while B cells are relatively sparse, in central nervous system (CNS) infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrate that radio-resistant, non-hematopoietic cells play a dominant role in shaping age-related features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of pMS, EAE in middle-aged adoptive transfer recipients is characterized by widespread microglial activation. Microglia from older mice express a distinctive transcriptomic profile, suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.

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Section: Discussionmentioning

confidence: 97%

Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

Atkinson

Jerome

Sas

et al. 2021

Preprint

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“…Although CD4 + T cells, both CD4 + Teff and CD4 + FoxP3 + Treg cells, are the traditional primary actors in MS/EAE disease pathogenesis and immunoregulation, emerging evidence shows that CD8 + T cells also have roles in both immunopathology and immunoregulation, either to exacerbate or mitigate brain inflammation during CNS autoimmunity 78,79 . Regarding the MS/EAE immunopathogenesis aspect, myelin-specific CD8 + T cells exacerbate brain, though not spinal cord, inflammation via a Fas liganddependent mechanism to promote lesion formation in the brain 80 . In addition, IL-17A secreting CD8 + T cells, termed Tc17 cells, in the CNS support Th17 cell-mediated autoimmune encephalomyelitis 56,57 .…”

Section: Discussionmentioning

confidence: 99%

Accumulation of Treg cells is detrimental in late-onset (aged) mouse model of multiple sclerosis

Wang

Thomas

et al. 2021

Preprint

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Although typically associated with onset in young adults, multiple sclerosis (MS) also attacks aged people, which is termed late-onset MS. The disease can be recapitulated and studied in the aged mouse model of experimental autoimmune encephalomyelitis (EAE). The onset of induced EAE is delayed in aged mice, but the disease severity is increased relative to standard EAE in young mice. Given that CD4+FoxP3+ regulatory T (Treg) cells play an ameliorative role in MS/EAE severity and the aged immune system accumulates Treg cells, failure of these cells to prevent or ameliorate EAE disease is enigmatic. When analyzing the distribution of Treg cells in EAE mice, the aged mice exhibited a higher proportion of polyclonal(pan) Treg cells and a lower proportion of antigen-specific-Treg cells in their periphery, but lower proportions of pan- and antigen-specific-Treg cells in the central nervous system (CNS). Furthermore, in the aged CNS, Treg cells exhibited a higher plasticity and T effector (Teff) cells exhibited a greater clonal expansion, which disrupted the Treg/Teff balance. Transiently inhibiting FoxP3 expression in peripheral Treg cells partially ameliorated the disease and corrected Treg distribution in the aged mice. These results provide evidence that accumulated aged Treg cells play a detrimental role in neuronal inflammation of aged MS.HighlightsQuestionCD4+ regulatory T (Treg) cells typically play an ameliorative role in multiple sclerosis (MS) onset and severity. However, why aged immune system has accumulated peripheral Treg cells, but the elderly has more severe MS symptoms?FindingsAged Treg cells cannot easily distribute to the CNS of aged EAE mice, and those aged Treg cells that did enter the CNS exhibited increased plastic features. However, transient inhibition of peripherally accumulated Treg cells corrected Treg distribution and partially ameliorated the disease in the aged mice.Conclusion and mechanistic insightsAccumulated aged Treg cells within an “inflammaging” condition do not play an ameliorative role but are potentially detrimental for inflamed CNS repair processes in aged EAE mice due to impeding the trafficking of immune cells into the inflamed CNS.

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“…Although inflammatory Th cell subsets have long been regarded as the main effectors of MS pathogenesis, an important pathophysiological role of CD8 + T cells has also recently been recognized. Histopathological studies of immune cell infiltrates in post-mortem brain tissues from MS patients showed a prevalence of CD8 + T cells compared to CD4 + T cells ( 105 , 145 ). Moreover, sRNA-seq analyses revealed a prominent oligoclonal expansion of CD8 + T cells in the peripheral blood and CSF of MS patients ( 146 , 147 ).…”

Section: Dysregulation Of Astrocyte Functions By Inflammatory T Cells...mentioning

confidence: 97%

“…The immunopathogenesis of MS relies on the recruitment of specific autoreactive Th cell subsets and CD8 + T cells within CNS where they are reactivated and secrete cytokines and chemokines that modulate the activity of several glial cells, including astrocytes ( 11 , 105 ). Among Th cells, Th1, Th17 and Th1-like Th17 cells have been identified as key players of MS pathogenesis, by producing one or more lineage-defining cytokines, which affect several astrocyte functions as discussed below ( Figure 1 ).…”

Section: Dysregulation Of Astrocyte Functions By Inflammatory T Cells...mentioning

confidence: 99%

Astrocytes and Inflammatory T Helper Cells: A Dangerous Liaison in Multiple Sclerosis

et al. 2022

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Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder of the central nervous system (CNS) characterized by the recruitment of self-reactive T lymphocytes, mainly inflammatory T helper (Th) cell subsets. Once recruited within the CNS, inflammatory Th cells produce several inflammatory cytokines and chemokines that activate resident glial cells, thus contributing to the breakdown of blood-brain barrier (BBB), demyelination and axonal loss. Astrocytes are recognized as key players of MS immunopathology, which respond to Th cell-defining cytokines by acquiring a reactive phenotype that amplify neuroinflammation into the CNS and contribute to MS progression. In this review, we summarize current knowledge of the astrocytic changes and behaviour in both MS and experimental autoimmune encephalomyelitis (EAE), and the contribution of pathogenic Th1, Th17 and Th1-like Th17 cell subsets, and CD8+ T cells to the morphological and functional modifications occurring in astrocytes and their pathological outcomes.

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Encephalitogenic and Regulatory CD8 T Cells in Multiple Sclerosis and Its Animal Models

Cited by 28 publications

References 109 publications

Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

Accumulation of Treg cells is detrimental in late-onset (aged) mouse model of multiple sclerosis

Astrocytes and Inflammatory T Helper Cells: A Dangerous Liaison in Multiple Sclerosis

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