PMID- 26122661
OWN - NLM
STAT- MEDLINE
DCOM- 20151026
LR  - 20230207
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 212
IP  - 8
DP  - 2015 Jul 27
TI  - Therapeutic antiviral T cells noncytopathically clear persistently infected 
      microglia after conversion into antigen-presenting cells.
PG  - 1153-69
LID - 10.1084/jem.20142047 [doi]
AB  - Several viruses can infect the mammalian nervous system and induce neurological 
      dysfunction. Adoptive immunotherapy is an approach that involves administration 
      of antiviral T cells and has shown promise in clinical studies for the treatment 
      of peripheral virus infections in humans such as cytomegalovirus (CMV), 
      Epstein-Barr virus (EBV), and adenovirus, among others. In contrast, clearance of 
      neurotropic infections is particularly challenging because the central nervous 
      system (CNS) is relatively intolerant of immunopathological reactions. Therefore, 
      it is essential to develop and mechanistically understand therapies that 
      noncytopathically eradicate pathogens from the CNS. Here, we used mice 
      persistently infected from birth with lymphocytic choriomeningitis virus (LCMV) 
      to demonstrate that therapeutic antiviral T cells can completely purge the 
      persistently infected brain without causing blood-brain barrier breakdown or 
      tissue damage. Mechanistically, this is accomplished through a tailored release 
      of chemoattractants that recruit antiviral T cells, but few pathogenic innate 
      immune cells such as neutrophils and inflammatory monocytes. Upon arrival, T 
      cells enlisted the support of nearly all brain-resident myeloid cells (microglia) 
      by inducing proliferation and converting them into CD11c(+) antigen-presenting 
      cells (APCs). Two-photon imaging experiments revealed that antiviral CD8(+) and 
      CD4(+) T cells interacted directly with CD11c(+) microglia and induced STAT1 
      signaling but did not initiate programmed cell death. We propose that 
      noncytopathic CNS viral clearance can be achieved by therapeutic antiviral T 
      cells reliant on restricted chemoattractant production and interactions with 
      apoptosis-resistant microglia.
FAU - Herz, Jasmin
AU  - Herz J
AD  - National Institute of Neurological Disorders and Stroke, National Institutes of 
      Health, Bethesda, MD 20892.
FAU - Johnson, Kory R
AU  - Johnson KR
AD  - National Institute of Neurological Disorders and Stroke, National Institutes of 
      Health, Bethesda, MD 20892.
FAU - McGavern, Dorian B
AU  - McGavern DB
AD  - National Institute of Neurological Disorders and Stroke, National Institutes of 
      Health, Bethesda, MD 20892 mcgavernd@mail.nih.gov.
LA  - eng
GR  - R01 AR068983/AR/NIAMS NIH HHS/United States
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150629
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (CD11c Antigen)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (Stat1 protein, mouse)
RN  - 45PG892GO1 (Evans Blue)
SB  - IM
CIN - J Exp Med. 2015 Jul 27;212(8):1141-2. PMID: 26216603
MH  - Analysis of Variance
MH  - Animals
MH  - Antigen-Presenting Cells/*immunology
MH  - CD11c Antigen/metabolism
MH  - Evans Blue
MH  - Flow Cytometry
MH  - Immunohistochemistry
MH  - Immunotherapy, Adoptive/*methods
MH  - Lymphocytic Choriomeningitis/immunology/*therapy
MH  - Lymphocytic choriomeningitis virus/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microarray Analysis
MH  - Microglia/*virology
MH  - STAT1 Transcription Factor/metabolism
MH  - Signal Transduction/immunology
MH  - T-Lymphocytes/*cytology/*immunology
PMC - PMC4516789
EDAT- 2015/07/01 06:00
MHDA- 2015/10/27 06:00
PMCR- 2016/01/27
CRDT- 2015/07/01 06:00
PHST- 2014/10/29 00:00 [received]
PHST- 2015/06/04 00:00 [accepted]
PHST- 2015/07/01 06:00 [entrez]
PHST- 2015/07/01 06:00 [pubmed]
PHST- 2015/10/27 06:00 [medline]
PHST- 2016/01/27 00:00 [pmc-release]
AID - jem.20142047 [pii]
AID - 20142047 [pii]
AID - 10.1084/jem.20142047 [doi]
PST - ppublish
SO  - J Exp Med. 2015 Jul 27;212(8):1153-69. doi: 10.1084/jem.20142047. Epub 2015 Jun 
      29.