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Bystander killing of neurons by cytotoxic T cells specific for a glial antigen
Author(s) -
McPherson Scott W.,
Heuss Neal D.,
Roehrich Heidi,
Gregerson Dale S.
Publication year - 2005
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20298
Subject(s) - biology , cytotoxic t cell , astrocyte , microbiology and biotechnology , retinal , retina , neuroglia , antigen , adoptive cell transfer , immunology , cd8 , neuron , ctl* , neuroscience , t cell , immune system , central nervous system , in vitro , genetics , biochemistry
To explore pathways to neuron loss in inflammatory diseases, transgenic mice expressing β‐galactosidase (β‐gal) in either astrocytes or photoreceptor cells, or both, were inoculated with activated, β‐gal‐specific cytotoxic CD8 T lymphocytes (CTLs). β‐gal‐positive astrocytes in brain were rapidly attacked, with particular damage in cerebellum. Substantial loss of cerebellar granule cells was found, even though these neurons did not express β‐gal. The small number of β‐gal‐positive retinal astrocytes present in these mice was also rapidly destroyed by transferred CTLs, but without detectable consequences for retinal neurons. However, in mice with photoreceptor cell‐specific β‐gal expression, near‐total destruction of photoreceptor cells was produced by CTL transfer. Attack on photoreceptor cells displayed minimal inflammation, and onset was a week later than onset of astrocyte‐directed disease. CTL transfer into F 1 mice expressing β‐gal in both astrocytes and photoreceptor cells confirmed that pathogenesis directed against antigen expressed in glia versus neurons proceeded in two distinct, independent phases. β‐gal‐positive retinal astrocytes were severely affected by 5 days post‐transfer, followed by rapid resolution. Photoreceptor cells in the same retina were unaffected until 12 days post‐transfer. The susceptibility of photoreceptor cells was not enhanced by the prior CTL attack on β‐gal‐expressing retinal astrocytes. The results demonstrate that extensive bystander killing of neurons can occur in vivo as a result of direct CTL attack on surrounding astrocytes. Antigen‐expressing retinal neurons were also efficiently killed by CTLs, but by a mechanism that was substantially delayed and dissociated from the killing of retinal astrocytes. © 2005 Wiley‐Liss, Inc.