title: Lymphocytes with cytotoxic activity induce rapid microtubule axonal destabilization independently and before signs of neuronal death.
abstract: MS (multiple sclerosis) is the most prevalent autoimmune disease of the CNS (central nervous system) historically characterized as an inflammatory and demyelinating disease. More recently, extensive neuronal pathology has lead to its classification as a neurodegenerative disease as well. While the immune system initiates the autoimmune response it remains unclear how it orchestrates neuronal damage. In our previous studies, using in vitro cultured embryonic neurons, we demonstrated that MBP (myelin basic protein)-specific encephalitogenic CD4 T-cells induce early neuronal damage. In an extension of those studies, here we show that polarized CD4 Th1 and Th17 cells as wells as CD8 T-cells and NK (natural killer) cells induce microtubule destabilization within neurites in a contact-independent manner. Owing to the cytotoxic potential of these immune cells, we isolated the luminal components of lytic granules and determined that they were sufficient to drive microtubule destabilization. Since lytic granules contain cytolytic proteins, we determined that the induction of microtubule destabilization occurred prior to signs of apoptosis. Furthermore, we determined that microtubule destabilization was largely restricted to axons, sparing dendrites. This study demonstrated that lymphocytes with cytolytic activity have the capacity to directly drive MAD (microtubule axonal destabilization) in a bystander manner that is independent of neuronal death.
authors.affiliation: BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, WI 53226, USA.
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Miller
authors.forename: Leah P
authors.initials: LP
authors.lastname: Shriver
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Bodiga
authors.forename: Avijit
authors.initials: A
authors.lastname: Ray
authors.forename: Sreemanti
authors.initials: S
authors.lastname: Basu
authors.forename: Rajiv
authors.initials: R
authors.lastname: Ahuja
authors.forename: Arundhati
authors.initials: A
authors.lastname: Jana
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
authors.forename: Bonnie N
authors.initials: BN
authors.lastname: Dittel
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D001426:Bacterial Proteins / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004622:Embryo, Mammalian; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D053804:Granzymes / Q000172:deficiency; D020287:In Situ Nick-End Labeling; D007694:Killer Cells, Natural; D008164:Luminescent Proteins / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D004676:Myelin Basic Protein / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D054353:Perforin / Q000172:deficiency; D018417:Th1 Cells; D058504:Th17 Cells / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D017077:Culture Media, Conditioned; D016207:Cytokines; D008164:Luminescent Proteins; D004676:Myelin Basic Protein; C054562:yellow fluorescent protein, Bacteria; D054353:Perforin; D053804:Granzymes