Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy

Dan Xu, Andrew P. Robinson, Toshiyuki Ishii, D'Anne S. Duncan, Tord D Alden, Gwendolyn E. Goings, Igal Ifergan, Joseph Robert Podojil, Pablo Penaloza-MacMaster, Jennifer A Kearney, Geoffrey T Swanson, Stephen D Miller*, Sookyong Koh

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both γδ T cell- and IL-17RA-deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies.

Original languageEnglish (US)
Pages (from-to)1169-1186
Number of pages18
JournalJournal of Experimental Medicine
Volume215
Issue number4
DOIs
StatePublished - Apr 1 2018

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Regulatory T-Lymphocytes
Interleukin-17
Granulocyte-Macrophage Colony-Stimulating Factor
Pediatrics
T-Lymphocytes
Brain
Seizures
Encephalomalacia
Malformations of Cortical Development
Immunomodulation
Status Epilepticus
Kainic Acid
Adaptive Immunity
Myeloid Cells
Epilepsy
Leukocytes
Drug Resistant Epilepsy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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title = "Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy",
abstract = "The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both γδ T cell- and IL-17RA-deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies.",
author = "Dan Xu and Robinson, {Andrew P.} and Toshiyuki Ishii and Duncan, {D'Anne S.} and Alden, {Tord D} and Goings, {Gwendolyn E.} and Igal Ifergan and Podojil, {Joseph Robert} and Pablo Penaloza-MacMaster and Kearney, {Jennifer A} and Swanson, {Geoffrey T} and Miller, {Stephen D} and Sookyong Koh",
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T1 - Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy

AU - Xu, Dan

AU - Robinson, Andrew P.

AU - Ishii, Toshiyuki

AU - Duncan, D'Anne S.

AU - Alden, Tord D

AU - Goings, Gwendolyn E.

AU - Ifergan, Igal

AU - Podojil, Joseph Robert

AU - Penaloza-MacMaster, Pablo

AU - Kearney, Jennifer A

AU - Swanson, Geoffrey T

AU - Miller, Stephen D

AU - Koh, Sookyong

PY - 2018/4/1

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N2 - The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both γδ T cell- and IL-17RA-deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies.

AB - The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both γδ T cell- and IL-17RA-deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies.

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