Neuroinflammation by cytotoxic T-lymphocytes impairs retrograde axonal transport in an oligodendrocyte mutant mouse.
Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage.
Department of Neurology, Section of Developmental Neurobiology, University of Würzburg, Würzburg, Germany.
Chi Wang
CW
Ip
Antje
A
Kroner
Janos
J
Groh
Marianne
M
Huber
Dennis
D
Klein
Irene
I
Spahn
Ricarda
R
Diem
Sarah K
SK
Williams
Klaus-Armin
KA
Nave
Julia M
JM
Edgar
Rudolf
R
Martini
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D053804:Granzymes / Q000378:metabolism; D006579:Heterozygote; D007107:Immune System; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000473:pathology; D009836:Oligodendroglia / Q000166:cytology*; D011510:Proteolipids / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*
D011510:Proteolipids; D053804:Granzymes