TY - JOUR
T1 - Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures
AU - Chang, Julia W.
AU - Reyes, Samuel D.
AU - Faure-Kumar, Emmanuelle
AU - Lam, Sandi K.
AU - Lawlor, Michael W.
AU - Leventer, Richard J.
AU - Lew, Sean M.
AU - Lockhart, Paul J.
AU - Pope, Kathryn
AU - Weiner, Howard L.
AU - Salamon, Noriko
AU - Vinters, Harry V.
AU - Mathern, Gary W.
AU - Fallah, Aria
AU - Owens, Geoffrey C.
N1 - Funding Information:
This study was funded by NIH grant NS107884 and The RE Children’s Project. CytTOF was carried out by The Jonsson Comprehensive Cancer Center Janis V. Giorgi Cytometry Core Facility, RNA sequencing was carried out by The Technology Center for Genomics, Bioinformatics, Department of Pathology and Laboratory Medicine, and HLA typing by The UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine. The nanoString® assays were performed at the UCLA IMT Core/Center for Systems Biomedicine, which is supported by NIH grant P30DK041301. Post-surgery blood draw involved The Clinical and Translational Research Center, which is supported by NIH National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881.
Publisher Copyright:
© Copyright © 2021 Chang, Reyes, Faure-Kumar, Lam, Lawlor, Leventer, Lew, Lockhart, Pope, Weiner, Salamon, Vinters, Mathern, Fallah and Owens.
PY - 2021/4/6
Y1 - 2021/4/6
N2 - Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.
AB - Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.
KW - Rasmussen encephalitis
KW - T cell receptor
KW - epilepsy
KW - focal cortical dysplasia
KW - tuberous sclerosis complex
UR - http://www.scopus.com/inward/record.url?scp=85104563537&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104563537&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.664344
DO - 10.3389/fimmu.2021.664344
M3 - Article
C2 - 33889159
AN - SCOPUS:85104563537
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 664344
ER -
